Ichthyosis Linearis Circumfiexa (ILC) is a rarely seen autosomal recessive keratinization disorder and is characterized by erythematous, polycystic, plaques with 'double-edged' scales. Its histological features resemble psoriasis. A triad of ichthyosis (usually Ichthyosis Linearis Circumfiexa), trichorrhexis invaginata (a distinctive hair shaft disorder) and atopy is named as Netherton syndrome. Herein, we report a 12 year-old girl presenting with ILC not accompanied with typical atopy findings and hair shaft disorder.
Hydrops fetalis is a severe clinical feature characterized by abnormal fluid accumulation in at least two body compartments and subcutaneous edema (7). Edema is usually in the fetal subcutaneous tissue, and vary from mild to generalized types. Even there may be a massive edema that can be enough to cause the extremities to remain in the extension position (2). Hydrops can sometimes result in miscarriage or the baby may be lost in the intrauterine period, (11). The most common type is non-immune hydrops. Chromosomal, cardiovascular, thoracic and infectious causes are among the most frequent causes of non-immune hydrops (7).Herein we present a case with Down syndrome who developed massive hydrops fetalis due to liver hamartoma and transient myeloproliferative disorder in the antenatal period.A baby, born with caesarean section at the 38th weeks of pregnancy as the 3rd alive baby of the mother's 3rd pregnancy, with a birth weight of 3320 grams, was intubated and has been resuscitated due to the lack of spontaneous respiration and heartbeat. The patient was transferred to neonatal intensive care unit (NICU) after resuscitation. APGAR scores at 1st and 5,h minutes were 2 and 4, respectively. The baby was mechanically ventilated in the NICU. On physical examination, massive edema, toughened cutaneous and subcutaneous tissues was present. The limbs were in the extension position due to this extensive edema. In addition, there was tachypnea and, hepatosplenomegaly (5-6 cm under the arcus costarium). The baby had the clinical features of Down syndrome, which was antenatally diagnosed. Chromosomal analysis showed 47, XY, +21 (trisomy 21). Laboratory evaluation revealed anemia, hypoalbuminemia, hyperuricemia and prolonged coagulation panel. Therefore albumin infusion and allopurinol treatment were started. The patient was transfused with erythrocyte suspension because of anemia and administered vitamin K and fresh frozen plasma therapy because of prolonged coagulation test results. Rasburicase therapy was given due to continuous elevation of uric acid levels. Peritoneal dialysis was administered since the urea and creatinine levels increased. The blast cells in the peripheral blood smear examination were considered to be associated with transient myeloproliferative disorder. Flow cytometry analysis revealed acute myeloblastic leukemia (AML), M7. Abdominal ultrasound showed a liver hamartoma 4X3.5 cm in size. Enlargement of the right cavities, pulmonary hypertension, severe tricuspid valve regurgitation, pulmonary insufficiency (3rd grade), mitral regurgitation (3rd grade), and aortic regurgitation (3rd grade) were observed by echocardiography. Because the patient had pulmonary hypertension, sildenafil treatment was first started, but was changed to iNO. In the following period the patient had hypotension and heart failure, so dopamine infusion was started. The newborn's general condition got worse progressively in the following period and he died on the fourth day of hospitalization.Non-immune hydrops is the most common type of hydrops fetalis, and has a quite high mortality (11). Different incidence rates between 1.3/1000 and 6/1000 have been reported in various studies so far (11). In addition to cardiac, hematologic, chromosomal, serological and metabolic studies, also imaging techniques are required to assess the structural abnormalities in these patients (2). Primary hepatic tumors are rarely seen in prenatal period as a cause of hydrops. Hepatic hamartomas, mesenchymal tumor of the liver, have been reported to cause hydrops in a few case report previously (3). Some other abnormalities such as liver hemangioma, hepatic fibrosis, cystic liver lesions and hepatic vasculary malformations have been showed to lead hydrops in fetal life (1, 8). Chromosomal disorders like Turner Syndrome and Down Syndrome have been reported as the probable causes of hydrops in the 32-78% of the cases with early fetal presentation (
Osteocraniosplenic syndrome-hypomineralized skull with gracile long bones and splenic hypoplasia: a case report and literature review: We report herein an intrauterine growth-restricted preterm nwonate with a lethal bone dysplasia characterized by severe hypomineralization of the skull, absent medullary lucency flared metaphyses fishbone-like diaphysis and overtubulated long vones. Dysmorphic features included flat facies, bulging forehead, vevus flammeus, depressed nasas bridge, short philtrum, inverted U-shape mouth, mild micrometic dwarfism, and brachydactyly. The infant's lungs and spleen were hypoplastic. The findings are compatible with the 19 previously reported cases that used different terminology: osteocraniostenosis, gracile bone disorders and osteocraniosplenic syndrome. We present the clinical, pathological and cytogenetic findings of this rare disorder.
The Joubert syndrome is characterized by hypotonia, ataxia, facial dysmorphism, abnormal eye movement, irregular breathing pattern and cognitive impairment. The molar tooth sign is the pathognomonic midbrain-hindbrain malformation for Joubert syndrome. Joubert syndrome and related disorders (JSRD), are the clinically and genetically heterogen disorders in which the obligatory hallmark is the molar tooth sign (MTS). In this report, it was described the association of the molar tooth sign, absence of pituitary gland and corpus callosum agenesis on an infant with JSRD. To the best of our knowledge, this is the first case diagnosed as JSRD and panhypopituitarism without features of OFD VI.
The appearance of untreated severe hydrocephalus with long-term survival is infrequent; here we report a case with these characteristics, mild neurological alterations and kidney and skeletal anomalies. A female patient showed severe hydrocephalus (initially mistaken with hydranencephaly) at 4 years old and left kidney ectopia (initially mistaken with renal agenesis); however, she was derived to the neurology service until she was 12 years old, when she began to present migraine and seizures. At 13 years old the patient was diagnosed with arrested hydrocephalus secondary to aqueduct stenosis, and the seizures worsen thereafter from atonic seizures to complex partial seizures (at 14 years old), presenting generalized seizures at 15 years old. At 17 years old, the seizures were more frequent despite the anticonvulsant treatment and also presented automations, she was also diagnosed with genu recurvatinn and scoliosis. The seizures finally diminished and partially controlled at 19 years old. Despite a cerebral mantle < 2.0 cm at the computer tomography, the patient always presented a satisfactory intellectual development. In this case, the relatively good and long evolution of the severe hydrocephalus is probably related with the late-onset of the disease that permitted a better development of the brain; however, the worsening of the seizures after the hydrocephalus arrested, suggests that arrest is not necessarily associated with a compensation and better evolution of the disease, at least at the beginning of the process. The presence of kidney ectopia and skeletal alterations did not associate with a known genetic disease, however a possible inheritance mechanism is not discarded.
Dyskeratosis congenita (DC) is a rare genetic disease of telomere biology and is characterized by the classic triad of reticular skin pigmentation, dysplastic nails, and oral leukoplakia (4, 6,16). Autosomal dominant, autosomal recessive and X-linked recessive forms of the disease have been defined, and it is associated with the genes encoding telomerase and components of telomere-related proteins (12,15,17). The risk for progressive bone marrow failure, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), solid tumors (especially squamous cell carcinomas of the head/neck or anogenital cancers) and pulmonary fibrosis is increased (1,3). To date, mutations in the DKC1 (X-linked), TERT (autosomal dominant or autosomal recessive), TERC and TINF2 (autosomal dominant), NHP2, CTC1, NOP 10 and WRAP53 (autosomal recessive) genes have been identified as causing DC (14). The most widely known genetic model is the X-linked recessive form, and it is associated with a missense mutation of the DKC1 gene. This gene encodes a nucleolar protein (dyskerin) that is essential for ribosome biogenesis and telomere maintenance (18). We present here the molecular and cl inical findings of a case of DC. In our case, a hemizygotic mutation in the DKC1 gene (c.227C>T, p.Ser76Leu) was detected.The 20-year-old male presented herein was born weighing 2100 gr as the second live birth of the second pregnancy of a 22-year-old mother. The boy did not have any hallmarks reported in his prenatal history. He had frequent infections. The boy, whose nails did not grow for approximately 10 years, had pigmentation anomalies in the skin for about the same period of time. The patient was diagnosed with splenomegaly 2 years ago. He had complaints of anemia, imperception and failure to gain weight for a long time. In his physical examination, he had blepharitis, tooth decay, microcephaly, sparse hair, moustache and beard, cachectic appearance and pes planus, in addition to a classical triad of symptoms: reticular, hyperpigmented skin lesions in the neck and shoulders, leukoplakia of the tongue, and dystrophy in the nails of the hands and feet (Fig. la-c). All of his hand fingerprints were absent. In the gastroscopic examination, he exhibited esophageal stenosis (web) at the cervical level and grade 3 esophageal varices in the distal esophagus. He exhibited pancytopenia in the complete blood count analysis and osteoporosis and osteopenia in the DEXA scan. Portal hypertension was observed in the portal vein Doppler US as well as periportal fibrosis in the liver, massive splenomegaly and ascites in the abdomen. His echocardiogram revealed normal cardiac function. His 42-year-old mother had prematurely gray hair and dystrophic toe nails. The case was assessed as DC due to these findings. The patient exhibited short telomeres and a hemizygotic mutation in the DKC1 gene (c.227C>T, p.Ser76Leu), and his mother had the same heterozygous mutation. No mutations were found in the father.Abnormal skin pigmentation, nail dystrophy, bone marrow failure and leukoplakia are among the major clinical characteristics of dyskeratosis congenita. Other well-defined somatic features include epiphora, learning disability/growth retardation/mental retardation, pulmonary disease, short stature, excessive tooth decay/tooth loss, esophageal stenosis, premature hair loss/prematurely gray hair/sparse eyebrow, malignancy, intrauterine growth retardation, liver disease/peptic ulcer/ enteropathy, ataxia/cerebellar hypoplasia, hypogonadism/undescended testes, microcephaly, urethral stenosis/phimosis, osteoporosis/aseptic necrosis/scoliosis and deafness. For a diagnosis of DC, the patient must have 2 or more of the 4 major features and 2 or more of the somatic features (7). Our case satisfied the diagnostic criteria of DC.The most commonly reported form of DC is the X-linked form. Mutations in the DKC1 gene result in DC cases of varying severity. While the children appear normal at birth, the classical triad of mucocutaneous lesions are observed in the first decade of life, bone marrow failure develops in the second decade of life, and death occurs due to bone marrow failure and complications of bleeding and infections in the third decade (2, 6). …
Rhizomelic chondrodysplasia punctata (RCDP) is a rare autosomal recessive disorder characterized by stippled epiphyses and rhizomelic shortening of the long bones within the heterogenous group of chondrodysplasia punctata (1). There are few reports discussing the antenatal diagnosis of RCDP. We report prospective antenatal diagnosis of a case with RCDP in a fetus without family history.A 30 year old multigravid was referred to our clinic at 29 weeks gestation following ultrasound detection of short femur length. The parents had first degree consanguinity and the family had no history of skeletal dysplasia. Ultrasonographic evaluation revealed that the femur and tibias were below the 3rd centile. Multiple punctuations were detected in proximal and distal epiphyses of the humeri and femur (Fig. la-lb). The remaining long bones were appropriate in length for gestational age. Nasal hypoplasia, micrognatia and increased prenasal thickness were detected in the fetal profile. No additional malformation was detected. Diagnosis of RCDP was suspected due to the findings of stippled epiphyses in the context of rhizomelic limb shortening. Fetal blood sampling analysis revealed PEX 7 mutation in consistent with Type 1 RCDP. Follow up ultrasonographic examination at 32 weeks 6 days of gestation demonstrated the previous findings detected earlier. Cesarean section (CS) was performed at 39 weeks gestation with the indication of previous CS. Morphologic features of the newborn were flat face, hypertelorim, broad nose, antevert nares, long and smooth philtrum, down turned comers of the mouth, broad ear nodules and short neck (Fig. lc). Postnatal radiographs revealed shortening of the both humeri and femoras and stippling of long bones (Fig. Id).Since RCDP is inherited in an autosomal recessive manner, there will be a negative family history for most cases. So the diagnosis can be done if a family history exists but cases have been reported even without such a history. Similar to the present case; Gendal et al. reported a case of rhizomelic chondrodysplasia punctata in a dichorionic twin, in which one was noted to have rhizomelic limb shortening at 25 weeks of gestation. The humeri were shaped like dumbbells and multiple hyperechoic foci were noted in the humeral and proximal femoral epiphyses. Diagnosis of rhizomelic chondrodysplasia punctata was confirmed in this twin by demonstration of absent alkyl-dihydroxyacetone phosphate synthase activity in cultured skin fibroblasts after postmortem examination (2). Also Hertzberg et al. described prospective antenatal diagnosis of RCDP in a fetus with no family history. In the light of sonographic findings including rhizomelic shortening in combination with premature ossification and stilliping of multiple epiphyses. Amniosynthesis revealed deficient fibroblast peroxisomal plasmalogen synthesis enzymes, which confirmed the diagnosis (3).Nasal hypoplasia, micrognatia and increased prenasal thickness were the only additional sonographic findings in the present case. Basbug et al. reported sonographic diagnosis of a case with type 1 RCDP at 30 weeks of gestation with bilateral cataracts (4). …
Pallister-Killian syndrome (PKS, OM1M #601803) is a rare dysmorphic syndrome characterized by tissue-limited mosaicism for tetrasomy 12p because of a supernumerary isochromosome for the short arm 12, +i(12p) (6). Whereas, the clinical information about PKS generally comes from individual case reports, in 2012 Wilkens et al, reported their 59 newly diagnosed case series with PKS and reviewed previously reported 152 cases (10). In postnatal cases PKS is characterized by craniofacial dysmorphism, pigmentary skin anomalies, congenital heart defects, diaphragmatic hernia, hypotonia, intellectual disability, and epilepsy (5). Prenatally detected PKS cases are rare and can create difficulties in prenatal diagnosis due to tissue specific mosaicism and clinical diversities in the cases reflecting tissue specific mosaicism and mosaicism ratios in the affected tissues.Here, we present a healthy 39-years-old, Indonesian, gravida 3 para 2 woman who was referred for amniocentesis at 18 weeks of gestation because of abnormal ultrasonographic screening including left-sided diaphragmatic hernia and right-sided cardiac deviation, absence of fluid-filled stomach, severe skin edema including prominent prenasal thickness and frontal bossing, polyhydramnios, rhizomelic short limbs, short digits and blunt feet, possible skeletal dysplasia and also the poor perinatal outcome of diaphragmatic hernia. This was her second marriage and both of her children from previous marriage were healthy. Additionally, there was no consanguinity with her 31 year-old husband with Turkish etnicity. The couple's personal and family histories were unremarkable. Cytogenetic analysis was recommended to the family due to abnormal ultrasonographic findings. Amniocentesis was performed at 18th week of the gestation. Conventional cytogenetic analysis by using GTG banding were performed on metaphase cells obtained by two independently cultivated amniocytes showed 47,XY,+i(12)(plO) [20] karyotype in analysed metaphases (Fig. 1). Parental karyotypes were normal. Subtelomeric FISH analysis performed by using Chromoprobe multiprobe T system (Cytocell, Cambridge, UK) confirmed that the additional chromosome was an isochromosome of the chromosome 12 short arm and the fetus has tetrasomy of the chromosome 12 short arm (Fig. 2). The parents opted to terminate the pregnancy and fetal autopsy proposal was denied by the family. It was reported that false-negative diagnostic result can occur in 55% (12/22) of the cases from blood lymphocyte cultures, 43% (3/7) from short-term cultures/direct preparations of chorionic villus sampling (CVS), 50% (1/2) from long-term cultures of CVS, and 12% (3/25) from amniocyte cultures in a meta-analysis of 28 PKS pre/postnatal cases (1). According to results reviewed by Chen et al., there is no single tissue that does not have a false-negative result. Therefore, Chen et al. 2007 recommended that in the cases suspected as having PKS, various tissues should be used sequentially for confirmation of the PKS diagnosis. Amniocentesis has the least false-negative rate for PKS diagnosis prenatally and therefore first evaluated cells must be amniocytes for prenatal diagnosis of PKS. However, in cases that amniocentesis does not confirm the PKS, chorionic villus sampling might be performed to confirm PKS diagnosis (1). Therefore, we choose the amniocentesis for prenatal diagnosis of our case with a suspected PKS. It has been also suggested that the abnormal cells with tetrasomy 12p in blood lymphocyte and amniocyte cultures are less stable than those in the fibroblast cultures derived from skin and other tissues, and the young cultures at early passage are likely to have more abnormal cells with tetrasomy 12p than the old cultures (8). In our case, we did not need to confirm the stability of tetrasomy 12p in another tissue due to non-mosaic form of the result. We thought that the results must be confirmed by using abort material after termination of the pregnancy but in our case it was not available because the termination was done in another city. …
Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder usually presenting between the ages of six months and two years, characterized by rapidly regression of cognitive and motor functions, axial hypotonia, gait disturbance, limb spasticity, cerebellar signs, optic atrophy and confirmed by PLA2G6 gene. PLA2G6 is causative of PL^Gd-associated neurodegeneration (PLAN), which is a subgroup of neurodegeneration with brain iron accumulation (NBIA). This group includes: 1) Infantile neuroaxonal dystrophy (INAD); 2) Atypical later-onset NAD; 3) Karak syndrome; 4) early onset dystonia-parkinsonism with cognitive impairment (2,5). INAD patients' progression is rapid and death occurs often at the end of the first decade (3,5).We would like to share a case experience of a 20 month-boy who was admitted to our clinic for difficulty in walking and frequent falls. He started walking and talking at the age of one. He couldn't make two words sentences. He had three siblings of whom one of them had similar findings. His sister' early psychomotor development was normal till 1 year of age. From age one, she stopped making progress and subsequently she developed seizures, mental regression, became bedridden and died. His other sister was at the age of 16 and brother was at the age of 6, their medical histories was unremarkable. The parents have a third-degree consanguinity. Neurological examination of ornease showed hypotonia and had areflexia. His initial MRI revealed insignificant vermin hypoplasia, whereas the following MRI after nine months revealed cerebellar vermian hypoplasia and apparent claval hypertrophy (Fig. 1). Metabolic screening tests were normal (tandem mass spectroscopy, very long chain fatty acid, plasma and urine aminoacids, transferrin isoelectric focusing for CDG). Electromyography (EMG) showed distal axonal type sensory-motor neuropathy. His visual examination was normal at the beginning. But control visual examination showed optic atrophy without strabismus and nystagmus. Delayed visual evoked potentials (VEP) was seen. By these findings, a genetic evaluation was initiated after obtaining appropriate parental consent. To make a precise diagnosis, we then performed targeted Next Generation Sequencing (NGS) of related PLA2G6 gene. PLA2G6 gene sequencing analysis was performed using the MiSeq next generation sequencing (NGS) platform (Illumina, San Diego, CA, USA). Exons 1 to 17 of the PLA2G6 gene and their flanking splice site junctions were amplified using primers and protocols from PRIMER® - Primer Designer v.2.0 (Scientific & Educational Software Program). Obtained sequences were compared with the reference sequences deposited in the public database (NM_003560). Sequencing analysis showed missense mutation in exon 14 of PLA2G6 gene (c,1756G>A, p.G586R). The proband was homozygous whereas both parents were heterozygous mutant allele. Detected mutation occurred at highly conserved sites in the multi-sequence alignment and is predicted by three different in silico analyses: the SIFT (Sorting Intolerant From Tolerant) program (http://sift.jcvi.org/), Mutation Taster program (http://www.mutationtaster.org) and the PolyPhen2 program (http://genetics.bwh. harvard.edu/pph2/) approaches to be non-tolerated changes that affect protein function. Molecular analysis of PLA2G6 (gene sequencing) gene demonstrated a novel homozygous p.G586R (c.1756G>A) mutation. By now he is 38 months and unable to walk, can sit without support only a few minutes. He only says a word and has bulbar dysfunction (drooling).Infantile neuroaxonal dystrophy is RL42G6-associated neurodegeneration (PLAN) which comprises a continuum of four phenotypes with overlapping clinical and radiologic features (2,5). PLA2G6 is located at chromosome 22ql3.1. and encodes IPLA2-VI, calcium independent phospholipase and dysfunction of it causes neurodegeneration and brain-iron dyshomeostasis (7, 8). Pathological features are axonal swelling and storage of spheroids throughout the central nervous system and peripheral tissues. …
Oculo-dento-digital dysplasia (ODDD) is a rare autosomal dominant disease characterized by a pleiotropic phenotype that primarily affects the eye, face, dentition and limb development with high level of penetrance and phenotypic variability ( 10). Diagnostic criteria of this disorder are facial anomalies involving ocular alterations with hypotelorism, microphtalmia and microcomea, pinched nose with hypoplastic nares and prominent columella, enamel hypoplasia and syndactyly type III, defined by bony and/or cutaneous fusion of fourth and fifth fingers and toes. Less frequent malformations including neurologic, hair and skin abnormalities can be observed as well (11,12). Neurologic manifestations in the ODDD are variable and include dysarthria, neurogenic bladder, bowel disturbances, spastic paraparesis, anterior tibial muscle weakness, and ataxia. They are classically exceptional during infancy and have a progressive onset by the second decade of life (9). In addition, intrafamilial variability of these neurologic signs has been reported in some familial ODDD cases with clinical anticipation through successive generations (2,11).ODDD is caused by mutations in GJA1 gene (Gap Junction Alpha 1) localized in 6q22.3. GJA1 involves two exons with encoding sequence starting at the exon 2. While, GJA1 has also one pseudogene GJAIP localized on 5q23, which has 97% sequence homology with GJA1 (11). This gene encodes the GJA1 protein, also named connexin 43 (Cx43), which belongs to the connexin proteins family. GJA1 is known to be the most ubiquitinously expressed connexin. All the connexin isoforms share the same architecture involving nine domains, among which six are relatively conserved, including four transmembrane and two extracellular loop domains, whereas, the three remaining domains, involving the intracytoplasmic loop domain and the amino and carboxyl termini are largely variable between connexins, and thus, are very likely responsible for specific function of each connexin isoforrn. The principal role of the connexin proteins is to constitute the gap junction channels, which are critical to electrical and metabolic intercellular exchanges, being at the base of physiologic equilibrium within different tissues and across different stages of life (13).In this study, we report the clinical and molecular findings in a three-generation Tunisian family with ODDD associated with neurologic manifestations.Table I summarizes clinical findings of the five affected individuals of this family.The proband was a female firstly referred to the department of congenital and hereditary diseases of the Charles Nicolle Hospital in Tunis for bilateral syndactyly of fingers and facial dysmorphism, seen at birth. Her family history revealed four other affected individuals having the same phenotypic anomalies. Three of them were examined and followed in our department. The pedigree of this non consanguineous Tunisian family is presented in Figure 1 (Fig. 1A).The proband (III1) was the first child of non-consanguineous parents. She was born at lull term after a normal pregnancy. Her Apgar scores were 9,10 at 1 and 5 minutes. Physical exam at birth was normal except for bilateral fingers syndactyly and facial dysmorphism. She was referred to our department at the age of one month. At that moment, all her measurements were at the 50th centile.Clinical examination showed bilateral complete syndactyly of the 4-5 fingers with camptodactyly and facial abnormalities including deep set eyes, microcomea, hypoplastic and anteverted nares with prominent columella and retrognathism. The rest of the physical exam was otherwise normal. Blood lymphocyte karyotype was normal. Radiographs of the hands revealed bilateral syndactyly of 4-5 fingers, with complete bone fusion of distal phalanges of the fourth and fifth rays. Physical examination of the proband's mother (112), maternal aunt (112), and maternal uncle (117) revealed the same facial characteristics, dental anomalies, bilateral 4-5 fingers syndactyly, and neurologic manifestations. …
Cytogenetically balanced reciprocal translocation with normal phenotype is the most common structural chromosomal rearrangement in human with approximately 1 in 500 and chromosomally unbalanced progenies or offsprings could be the products of these chromosomal rearrangements (4). Reciprocal translocation including two nonhomologous chromosomes will form a quadrivalent configuration in pachytene in meiosis I and will produce 32 types of gametes because of the alternate, adjacent-1, adjacent-2,3:1 or 4:0 segregations with apparently unbalanced chromosome complements while only two of the 32 are balanced (3,4), The frequency of the alternate and adjacent-1 segregations are far a way the others but the option of the 3:1 segregation, ended with interchange trisomy-monosomy and tersiyer trisomy-monosomy, is need to take consideration (3). Here, we present an interchange trisomy 21 case due to a 3:1 segregation derived from balanced maternal 17;21 translocation.The proband was a thirteen months old girl referred to our department because of the suspected trisomy 21. She was the third living child of healthy and nonconsanguineous parents who had six abortions in obstetric history. The proband was born at term by vaginal delivery and no invasive prenatal diagnosis test was performed in utero. Psychomotor development was severely delayed. Her head control developed at 8 months of age and she could sit without support at 12 months of age. At 13 months of age, weight, height, occipitofrontal circumference, and hand were 2250 gr («3 centile), 69 cm (3 centile), 42 cm (After cultivation of the peripheral blood lymphocytes, G-banding was performed and cytogenetic analysis ended with the derivative chromosomes 17 and 21 probably derived from a balanced reciprocal translocation between chromosome 17 and 21, with the two normal chromosomes 21 and one normal chromosome 17. Parental karyotyping showed that the mother was the translocation carrier, and the probandu0027s final karyotype reported as 47,XX,+21,t(17;21)(qll.2;q22.1)mat.The rates of unbalanced gametes could be different according to the nature of the chromosomes involved to the translocation or the length of the translocated segments, in the 3:1 category and a predisposition for 3:1 segregation in oogenesis (3,4). In addition to the interchromosomal effect in a reciprocal translocation affecting the segregation pattern of unrelated chromosomes, especially chromosome 21, our proband had a balance reciprocal translocation between chromosome 17 and the related small acrocentric (chromosome 21) would further exacerbated the situation (5). …
Distal trisomy 1 Oq syndrome is a rare syndrome associated with prenatal-onset growth deficiency, severe mental retardation, and craniofacial, skeletal, heart, and renal malformations and unusually cleft palate (2,4,5,6,9,16).In this letter we describe a case with partial 10q24.2->qter trisomy due to maternal insertional translocation which is rarely reported. The proband's phenotype was correlated to the points of breakage and was compared with previously reported cases with partial trisomy lOq.The two-month-old male proband, was referred with severe intrauterine growth retardation. His parents refused amniocentesis. He was born at 36 weeks of gestation by caesarean section because of breech presentation. All measurements were below the 3th centile for a preterm infant (birth weight was 1760 gr, whereas birth length and head circumference was 43 cm and 33 cm respectively). The primary concern after birth was respiratory distress due to dysmaturity; additionally cleft palate was diagnosed.On physical examination; hypertelorism, ear helix abnormality, a fishlike mouth, micrognathia, depressed nasal bridge, epicanthus, thin upper lip, clinodactyly and unusually cleft palate were observed. Brain ultrasound examination was normal. Ultrasound of the heart revealed atrial septal defect (4 mm) and muscular ventricular septal defect (4.2 mm). On ultrasound examination the renal parenchyma was hyperechogenic and there was bilateral grade I renal ectasia.The first pregnancy of the couple ended in spontaneous abortion and there was no history of phenotypically abnormal children.G banding by trypsin using Leishman (GTL) was performed. FISH (fluorescence in situ hybridization) was carried out using subtelomeric DNA probes specific for lOp, lOq and 15q (Chromoprobe-T, Vysis), and centromeric probe for chromosome 10 (Dl OZ 1) (Aiphasatellite, Vysis).Cytogenetic analysis of the proband revealed a male karyotype with an abnormal chromosome 15 with extra genetic material attached to the long arm (Fig. la). The mother had the same derivative chromosome 15 as in her son and an apparently deleted chromosome 10 in the long arm (Fig. lb-c). At this level of resolution there was no evidence for any reciprocal exchange of material from the derivative chromosome 15 to the derivative chromosome 10. We hypothesized a direct insertional translocation of apart of the long arm of chromosome 10 into the long arm of chromosome 15. FISH studies were done to demonstrate a balanced insertional translocation (15; 10) for mother. Not only the subtelomeric region of chromosome lOq but also subtelomeric region of chromosome 15q were shown on the derivative chromosome 15 (Fig. 2 a-b). On the other hand, the proband's mother did not have subtelomeric regions of lOq or 15q on the derivative chromosome 10 (Fig. 2 c-d). We concluded that the karyotype of the carrier mother was 46,XX,ins(15;10)(q26.3;q24.2q26.3) and the proband had 46,XY, der( 15)ins( 15; 10) (q26.3;q24.2q26.3) mat karyotype.Most cases with distal trisomy lOq syndrome result from an unbalanced reciprocal translocation or pure duplications. To our knowledge, there have been only two previous publications of partial trisomy lOq caused by direct insertion (1,8). Distal 1 Oq trisomy syndrome involves the 10q24->qter region. Clinical features are more severe in cases where the trisomy involves totally the region 10q24-^qter, mainly on account of renal and cardiovascular abnormalities (14). Long-term prognosis is usually poor, and approximately half of the reported patients died within the first year of life because of complications with congenital heart defects and other malformations. Clinical manifestations of distal lOq trisomy include high and large forehead, round and flat face, epicanthus, hypertelorism, fine eyebrows, anti-mongoloid slants, low-set ears, cleft palate, micrognathia, flat nasal bridge, short nose, bow-shaped mouth, microcephaly, hypotonia, joint laxity, clinodactyly, scoliosis, short neck, growth retardation, psycho-motor disorders, cardiac abnormalities, ocular abnormalities and renal abnormalities (2,4,6,9,11,16). …
Double trisomy mosaicism is a rare phenomenon in live births. Cases reported in literature exhibited mainly combinations of both autosomal and sex chromosomes trisomies. Described chromosomes are mostly the same as found in single trisomies, i.e. reported combinations included often, in addition to XXX or XXY, autosomal trisomy 21,18 or less often trisomy 13 (1,5,7). Double trisomies involving the sex extra chromosome X are the most prevalent ones with various combinations of autosomal and gonosomal trisomies. Out of these, 48,XXX,+21; 48,XXX,+18 are the most common presentations in female cases (6). Clinically, it appeared that, in most cases, the extra chromosome X had not contributed to any phenotypic abnormalities, basing on the phenomenon of chromosome X-inactivation involving the extra X chromosome in triple X cell lines. (1,7,11).Trisomy 8 has been rarely described in double trisomy in liveboms, and the most reported cases are found among chromosomal aneuploidies, being cause of spontaneous abortions (4, 8). Characteristic features of mosaic Trisomy 8 syndrome (T8MS), also known as Warkany syndrome, include facial dysmorphism with long face, prominent forehead, hypertelorism with epicanthic folds, deep-set eyes, wide nasal bridge, large low-set, and dysplastic ears, thick lower lip and micrognathia, advanced growth, developmental delay, and common skeletal deformities. Dermatoglyphics are the most characteristic of the syndrome with deep longitudinal plantar furrows (9). Moderate intellectual deficiency had been typically described in T8 mosaicism individuals, but some reported cases had normal intelligence (9).We report here the first case of double trisomy mosaicism 48,XXX, +8/46,XX in a 7 years old Tunisian girl, who had clinically facial dysmorphism, growth and motor milestones delay, hypotonia and febrile seizures. We followed this patient during 5 years.Our patient, a female, was the first child born of healthy and unrelated Tunisian parents. At the time of birth her mother and father were 23 years old and 33 years old, respectively. Their second child was a healthy 1-year-old boy with apparently normal development. There was no family history of congenital abnormalities or mental retardation. The pregnancy was not regularly followed but there were no remarkable events or exposure to chemicals during pregnancy period. The patient was born at full term (40 weeks of gestation) by spontaneous vaginal delivery. She had 9 and 10 points in Apgar scale at 1 and 5 minutes of life, respectively. Birth measurements were as following: weight was 2000 g, length 38 cm and head circumference 29 cm, being all under the 3rd percentile. She was hospitalized at birth for hypotrophy but no malformations or facial dysmorphism were noted. Her two first years were marked by hypotonia, growth failure, and psychomotor delay: she laughed at six months, sat at twelve months, stood up at eighteen months, and walked alone at the age of 2 years and 1/2. She was hospitalized several times because of repetitive respiratory tract infections with or without hyperthermic seizures. An electroencephalogram was performed three times but no abnormalities were found in the intercritical periods.She was referred to our department at the age of 2 years. During her first physical exam, growth parameters were as following: weight 8 kg (At the first examination, chromosomal analysis of our propositusu0027 lymphocytes showed a mosaic karyotype with two cell lines: a double trisomie cell line and a normal cell line (48,XXX,+8 [25]/46,XX [25]) (Fig. …
A female infant with developmental delay was found to have a compound 46,XX,del(2)(pll.2pl3),inv(2)(pll.2q31) G-banded karyotype in all 30 metaphases scored. Noticeably, the deletion appeared to have excised the 2pl2 band (Fig. 1A). Although parental karyotypes were normal, the father had 1/60 metaphases with an apparent reciprocal intrachromosomal insertion; i.e., in the exceptional cell the segments 2pl4p21 (two dark bands) and 2q22q31 (two dark and one intermediate grey bands) had switched positions (Fig. IB).Despite the lack of a full clinical description, the present patient appeared to be mildly affected. A comparison to 12 similar observations (13) further supports the notion chromatin loss mostly confined to band 2pl2 is compatible with a normal or nearly normal phenotype (1,14). Several complex rearrangements involving different chromosomes and entailing an interstitial imbalance have been ascribed to an unequal crossing-over placed at the base of an inversion or insertion loop in a carrier parent and leading to a deletion or duplication of a nearby segment (3,4). In addition, there is one familial inv(21 )(p 12q22.1 ) with an 1.7 Mb deletion within 21q22.11 (9) and a few de novo pericentric inversions coupled with loss of the segment distal to one breakpoint (5, 12, 15). More complex rearrangements including a pericentric inversion (2,10,11) are disregarded here.The double intrachromosome 2 insertion found in a single cell from the father, suggests a paternal germ-line mosaicism. A feasible meiotic pairing in the hypothetical clone with the rea(2) implies each inserted segment and their counterparts form one asynaptic loop; in turn, an unequal crossing-over between 2pll.2 in the normal chromatid and 2pl3 at the base of the insertion loop in the rearranged one followed by a canonical recombination still within 2pl3 and inversion of the segment 2pll.2q31 in the now deleted chromatid would account for the patient's rearrangement (Fig. 1C). Remarkably, Stevens et al. (14) have recently shown two pairs of LCRs flank the breakpoints of the ~9.4 Mb recurrent del(2)(pll.2pl2), a finding highlights the role of repetitive sequences in the genesis of certain interstitial imbalances mediated by unequal cross-over (3). Although no instance of a constitutional balanced double intrachromosomal insertion is on record, a chromosome 2 with both a paracentric inversion and pericentric insertion in a carrier father led, via one canonical and one unequal crossover, to a rec(2) in an affected child (8).The compound del(2p 12),inv(2)(p 11.2q31 ) karyotype here described recalls two chromosome 2 pericentric inversions of paternal transmission coupled with either a de novo 2pl2 deletion (6) or a de novo 2pl2p21 duplication (7). Based on Hoo's notions (3), Lacbawan et al. (6) asserted that the winding and coiling of chromatids at the base of a meiotic loop associated with a pericentric inversion may increase the possibility of unequal crossing-over.Notwithstanding the lack of conclusive evidence, our interpretation allows to ascribe the patient's compound rea(2) to the apparent double pericentric ins(2) found in one paternal cell rather than to dismiss such a concurrence as a curious coincidence.[Reference]REFERENCES1. BARBER J.C.K., THOMAS N.S., C0LL1NS0N M.N., DENNIS N.R.. L1EHR T, WEISE A.. BEUTZ B PFEIFFER L. KIRCHHOFFM., KRAG-OLSEN B LUNDSTEEN C.: Segmental haplosufficiency: transmitted deletions of 2pl2 include a pancreatic regeneration gene cluster and have no apparent phenotypic consequences. Eur. J. Hum. Genet., 2005, 13,283-291.2. GRANOT-HERSHKOVITZ E.. RAAS-ROTHSCHILD A.. FRUMKIN A., GRANOT D SILVERSTEINS.. ABELIOVICHD. …
(OMIM #249100) is a hereditary autosomal recessive autoinflammatory genetic disorder, which is characterized by short, self-resolving recurrent attacks of inflammation of serosal membranes. In this manner FMF results in acute fever, abdominal, joint pain, synovitis, myalgia and erythema. Between the attacks, patients are asymptomatic. Typically attacks last 12-72 hours with fever almost always present (5). Renal failure and renal amyloidosis are the most severe complications of FMF. MEFV gene mutations are responsible for the disease placed on chromosome 16pl3.3, which encodes pyrin contains 10 exons. It is mainly seen in eastern Mediterranean populations including Armenians, non-Ashkenazi Jews, Turks, and Arabs (8).Ordinarily autosomal recessive pattem of inheritance is usually evident, but it was found that patients with heterozygous mutation show clinical signs compatible with FMF (6). This syndrome shows a heterogeneous genetic basis. More than 314 mutations and polymorphisms have been reported to date (4).In this study, a Turkish non-consanguineous family with a total of four members clinically diagnosed as FMF, is investigated. For this purpose, all exons of MEFV gene (1-10) were amplified using PCR technic and whole exom sequencing analysis of the gene was carried out. A novel single base mutation in the coding region of MEFV gene, named K447M (p.Lys447Met, c.1340 A>T) heterozygote resulting in a mutated Pyrin/Marenostrin protein was detected. The proband also included M694V and R202Q mutation. Our results showed that in addition to the proband, her mother (M694V, R202Q), father (K447M) and brother (M694V,R202Q,K447M) have carried the mutation, too (Fig. 1). Clinical data of the patients are shown in Table I.To the best of our knowledge, this K447M (p.Lys447Met, c.1340 A>T) is a new mutation in exon 4 of the MEFV gene from a Turkish family. Only three sequence variants already have been reported on exon 4. This single base alteration seems to be a pathogenic according to the Mutation Taster and PolyPhen-2 bioinformatics programs. We thought that this novel mutation may provide important information for FMF pathogenesis.Amyloidosis is one of the most important causes of renal failure and related death especially among young adult patients. In the FMF disease, amyloidosis is developing a high probability if untreated. It was shown that amyloidosis is present in 7% -13% of the Turkish patients with FMF (7). Due to the widespread use of colchicine today, amyloidosis occurs in only a minority of patients with FMF. For this reason, early diagnosis and taking daily colchicine treatment of the patients has an important role in the prevention of FMF attacks and development of amyloidosis (2).In our current study, as the proband and her brother had complex genotype, the proband's father carried only K447M heterozygote mutation. He is 40 years old and he had intermittent fever and jabbing style chest pain story over 10 years. Cardiologic examination was normal and he had no history about such reflux or gastritis. According to these findings, K447M mutation leads to clinical findings of FMF, so colchicine therapy was started to the father in addition to our case and his answer to the colchicine will be followed by routine examination.FMF is diagnosed with clinical findings according to Tel Hashomer criteria's but studying of the MEFV gene with molecular analysis is needed for identifying or approving the diagnosis of FMF, especially in the atypical clinical situations as a late onset beginning, the absence of family history or ethnic background (3). Because of the absence of an accurate diagnostic test and nonspecific clinical manifestations, young children who had FMF may be subjected to extensive research, such as laparotomy, before the patient was correctly diagnosed with FMF.Molecular diagnostic testing for FMF is a non-invasive, high sensitive and specific method to be used for the correct diagnosis before the emergence of all clinical symptoms of disease. …
Neurofibromatosis type I (NF1) is caused by heterozygous mutation in the neurofibromin gene on chromosome 17qll and is inherited as autosomal dominant. Cafe-au-lait spots, intertriginous freckling, Lisch nodules, cutaneous neurofibromas, subcutaneous neurofibromas, plexiform neurofibromas, macrocephaly, and susceptibility to the development of benign and malignant tumors are among the most common or significant clinical features ofNFl (10). The prevalence ofNFl is estimated to range from 1/2190 to 1/7800 (12).Of importance related to present report, plexiform neurofibroma develops from nerve fascicles and can cause significant morbidity by growing along nerve and sometimes involving multiple nerve branches and plexuses. The growth rate is unpredictable and is associated with nearby soft tissue hypertrophy. The significant clinical importance of plexiform neurofibromas is their potential for transformation into malignant peripheral nerve sheath tumors beyond its cosmetic implications (3,9,12).Plexiform neurofibromas are rare (17%) among other neurofibroma types seen in NF1 patients, mostly occulting on trunk (43%) and head and neck region (42%), less in extremities (15%) (11). Male genital plexiform neurofibromas have very rare incidence of 2 per 361 patients diagnosed with NF1, mostly being reported in first and second decades of life (1,2,4-8). Here we report such rare case with penile plexiform neurofibroma. A 34-year-old male who had been previously diagnosed to have familial NF1 admitted to the urology clinics for penile mass grown progressively within last 5 years. Other than these mentioned above, his past medical history was uneventful. He had no complaints of erectile dysfunction, however difficulty in and pain with vaginal penetration, which have been severe during last months. Physical examination revealed 5x2 cm subdermal fixed, non-mobile penile mass with soft consistency on the right ventral side (Fig. 1) and multiple cafe au lait spots over trunk, mostly on the back. The MRI imaging penis revealed a minimally contrast enhanced 5.4x1.8 cm subcutaneous mass, with decreased signal intensity on T1WI and increased signal intensity on T2WI, on the right side of penis surrounding corpus cavernosum and spongiosum with unclear border between them and suspicious invasion of Buck fascia (Fig. 2). The patient was operated with right sided subcoronal circumferential incision and the soft tissue mass was adherent to right corpus cavemosum and partially to corpus spongiosum and was excised totally leaving no residual mass. The histopathological examination of the resected mass diagnosed it as plexiform neurofibroma (Fig. 3).In conclusion, neurofibromas in general and specifically plexiform form in the penis are very rare. In the literature, patients were mostly reported to admit to the clinics with the complaint of mass in the penis (4-8). Some others had, in addition, complaints of erectile dysfunction due to arterial stealing of the penile mass (1,2). …
