Kabuki make-up syndrome with genitourinary anomalies, ophthalmologic features and hyperpigmentation in an Egyptian child

We report a 3.5 year old male child, first in order of birth of healthy consanguineous Egyptian parents with typical characteristics of Kabuki make-up syndrome. The patient had microcephaly, high arched sparse eyebrows, hypertelorism, long palpebral fissures with eversion of the lateral third of the lower eyelids, bilateral ptosis, long eyelashes, blue sclera, depressed nasal bridge, broad nose with everted nares, and low set small deformed ears, thin lips, low post hair line, short neck, persistent fingertip pads, dysplastic nails, hypermobile joints, pigmented nevus on the back, lateral side of right foot and right leg and mild hypertrichosis over the lower back. Our patient had also a non-functioning left kidney, multiple chalazions in upper eyelids, enlargement of the glans penis, which were not reported previously, and moderate mental retardation

C syndrome with skeletal anomalies, mental retardation, eyelid chalazion, Bitot's spots and agenesis of the corpus callosum in an Egyptian child

We report a 2.5 year old female child, third in order of birth of healthy non consanguineous Egyptian parents with C syndrome. The patient had moderate mental retardation, trigonocephaly, protruding forehead, low anterior hair line, wide upslanted palpebral fissures, depressed nasal bridge, broad nose, high arched palate, microretrognathia, low set ears, short neck, scoliosis, hypertrichosis over the back, talipes equinovarus as well as interatrial septal defect. The patient had in addition chalazion in left lower eyelid as well as bilateral Bitot's spots most probably due to vitamin A deficiency. MRI brain revealed agenesis of the corpus callosum

Baraitser-winter syndrome: an additional Egyptian patient with skeletal anomalies, bilateral iris and choroid colobomas, retinal hypoplasia and hypoplastic scrotum

We report a 3.5 year old male child, second in order of birth of non consanguineous Egyptian parents with Baraitser-Winter syndrome [BRWS]. The patient had bilateral colobomas of the iris and choroid. Our patient had also retinal hypoplasia, which was not reported previously in this syndrome, bilateral congenital ptosis, hypertelorism, moderate mental retardation, short stature, short neck, hyperextensibility of the joints of the hands, talipes equinovarus, kyphoscoliosis and unilateral hypoplastic scrotum and testis

Selective screening in neonates suspected to have inborn errors of metabolism

Inborn errors of metabolism [IEM] have a high morbidity and mortality in neonates. Unfortunately, there is no nationwide neonatal screen in Egypt, so several cases may be missed. The aim of this work was to detect the prevalence of IEM among neonates with suspected IEM, and to diagnose IEM as early as possible in order to minimize morbidity and mortality in high risk neonates. This prospective study included 40 neonates admitted to the Elmahalla General Governmental Hospital Neonatal Intensive Care Unit [NICU] with sepsis like symptoms [lethargy, hypoactivity, poor suckling, and poor crying], convulsions, persistent metabolic acidosis, persistent vomiting, or previous sib death of unidentified cause [neonates with suspected IEM]. All included patients were subjected to detailed full history, through clinical examination, laboratory investigations, and metabolic screening by tandem mass spectrometry [MS/MS]. Other investigations for IEM including lactate, ammonia, and galactose 1 phosphate levels in the blood, as well as organic acids in urine were done according to each case. 13 patients [32.5%] were diagnosed as having IEM, 7 of them [53.8%] had urea cycle defect, 2 [15.4%] had maple syrup urine disease, while methylmalonic acidemia, fatty acid oxidation defect, mitochondrial disease, and galactosemia were diagnosed in one patient each [7.7%]. Out of these patients, 12 patients [30%] were discharged from NICU after therapy, and one patient [2.5%] died [the one who had mitochondrial disease]. Two patients were diagnosed as diseases other than IEM, one had hyperinsulinism and another one had congenital myopathy, while 2 patients were proved to be normal. Five patients [12.5%] were suspected to have IEM [tyrosinemia, mitochondrial disease, organic academia] 4 of them died before final diagnosis, and one transferred to another NICU. There was a significant difference between diagnosed and undiagnosed patients as regards history of sibling death]p = 0.012], plasma ammonia level [p = 0.002], and discharge from NTCU [p = 0.000]. Conclusion: IEM represent a high percent [32.5%] of neonates who had sepsis like symptoms, and when diagnosed, patients showed marked improvement after therapy. IEM should be considered in differential diagnosis of the sick neonates, and investigations, and management should be started rapidly to decrease morbidity, and mortality till nationwide screen for IEM is applied in Egypt

Berardinelli-Seip syndrome type 2 - An Egyptian child

We report a 2.5 year old male, first in order of birth of first cousin consanguineous parents with the typical features of Berardinelli-Seip congenital lipodystrophy 2 [BSCL2] since birth with moderate mental retardation. He had generalized lipodystrophy with various dermatologic and systemic manifestations. The patient looked older than his age with the loss of buccal pad of fat, hypertrichosis mainly on the back and lower limbs, thick scalp hair, mild prognathism, large hands and feet with prominent joints and muscular hypertrophy. Acanthosis nigricans was evident over the neck and both axillae inspite of the normal level of sugar and insulin. The abdomen was markedly prominent with mild hepatosplenomegaly and enlarged external genitals. Echo-cardiog-raphy demonstrated cardiac hypertrophy. Triglyceride level was high with reduced high density lipoproteins [HDL]

Trichorhinophalangeal syndrome II, expanding the clinical spectrum

We report a 4.5 year old Egyptian male child, fourth in the order of birth of healthy remote consanguineous parents. He has typical facial as well as skeletal features of Trichorhinopha-langeal syndrome [TRPS] II. The facial features included bilateral downward slanting palpebral fissures, bulbous nose, long filtrum, retromicrognathia, sparse hair in the scalp and thick eyebrows. The skeletal features included retarded bone age, cone shaped epiphyses of the phalanges and multiple exostoses. The patient has also growth retardation, moderate mental retardation and hyperlaxity of the right knee joint. However our patient has some features not reported in TRPS II patients. These included bilateral partial ptosis, long eye lashes, preauricular skin tag, short 2nd right finger, short metacarpals of both thumbs. So we have to expand the clinical spectrum. Karyotype demonstrated 46,XY,del 8[q23.3-q24.1]

Reduced penetrance in human inherited disease

For many inherited diseases, the same mutation is not always expressed in all persons who care it, moreover, when the mutation is expressed, it is not always expressed in the same way. These findings are the basis for the concepts of penetrance and expressivity. Understanding the factors that control penetrance of disease genes will provide insight into the fundamental disease processes and will help in genetic counselling. With the advancement of molecular genetics over the last few years, some of the underlying mechanisms of reduced penetrance have been elucidated. These include, mutation type, allelic variations in gene expression, epigenetic factors, gene-environment interplay, influence of age and sex, allele dosage, oligogenic and modifier genes, copy number variations as well as the influence of additional gene variants and the effect of single nucleotide polymorphisms. The aim of this review is to clarify factors affecting gene penetrance as well as some of the underlying molecular mechanisms in some genetic disorders

Bilateral absence of fifth ray in feet, cleft palate, malformed ears, and corneal opacity in a patient with Miller syndrome

Miller syndrome is one of the acrofacial dysostosis syndromes, which are characterized by malformations of the craniofacial region and limbs. A 26 month old male child, the product of healthy nonconsanguineous parents has many typical features of Miller syndrome. He has cleft lip and palate, malar hypoplasia, left crumpled cup shaped ear, and prominent nose together with the absence of the fifth ray in feet [postaxial] and fixation of interphalangeal joints of both thumbs [preaxial]. However the limb affection is bilateral and symmetrical against what is usually reported [bilateral with more affection of one side] and the micrognathia is very mild. Our patient has also bilateral corneal opacities as well as underdeveloped external genitals. There is phenotypic variability in Miller syndrome, and our patient may represent a new distinct subgroup in postaxial acrofacial dysostosis

Genotyping of mannose-binding lectin [MBL2] codon 54 and promoter alleles in Egyptian infants with acute respiratory tract infections

MBL2 gene polymorphisms affect serum concentration of mannose-binding lectin and are associated with infectious conditions. Acute respiratory tract infections are among the most prevalent infections in childhood with the highest incidence among children younger than 2 years. This study aimed at correlation between the occurrence of acute respiratory tract infections and the prevalence of MBL2 gene codon [54] and promoter variants among the Egyptian infants in the study. This case-control study included 25 neonates [0.21 +/- 0.19 months], 25 infants [9.65 +/- 8.5 months] with acute respiratory tract infection and normal control group. CBC, CRP and chest X-ray were done. DNA was extracted from peripheral blood. Genotypes of MBL gene codon 54-exon 1[G54D] were identified by PCR-RFLP analysis. MBL2 promoter genotyping was performed by allele-specific polymorphisms at -550 [H/L] and - 221[X/Y]. Incidence of LX promoter haplotype among the patients was [58%] [p < 0.05]. Homo-zygosity for codon [54] allele A [high expression activity] among patients was [72%] [p > 0.05]. Heterozygote codon 54 A/B genotype appeared more in patients [18%] [p < 0.05]. Mutant genotype [too low expression activity] was more in patients but the difference was insignificant. Collectively the mutant allele [glycine to aspartic acid, allele B] appeared in 28% of patients compared to 20% in control [p > 0.05]. YA/XA heterozygote promoter genotype was more prevalent among patients group [44%] [p < 0.05]. Low-expression promoters [XA/B] and [B/B] appeared more in the patients [20%] compared to [12%] among control group [p > 0.05]. Among ICU neonates, LX promoter was the most prevalent among all grades of respiratory distress [39.13%] followed by LY allele [34.78%]. In the infants group, LY allele was [52.1%] with equal distribution of LY and HY [23.91% each]. Although there is a significantly increased incidence of LX promoter coding for low serum MBL concentrations among the ARTI patients; the YA/XA heterozygote promoter genotype was more prevalent over the homozygote mutant genotype. Also, the heterozygote codon 54 A/B genotype was more prevalent in the group of patients compared to the control. This may be an example of heterosis [heterozygote advantage] which may support the concept of balanced polymorphism

Intrafamilial variability in Simpson-Golabi-Behmel syndrome with bilateral posterior ear lobule creases

We report a family having two male sibs with Simpson-Golabi-Behmel syndrome [SGBS]. Both have many typical features of the syndrome. These features included macrocephaly, macroglossia, post axial polydactyl of the left hand, bilateral low insertion of the thumb, multiple accessory nipples, hepatomegaly, and congenital heart. The patients have bilateral anterior helical ear pits, and characteristic posterior ear lobule creases. The older one has severe mental retardation and died at the age of 13 months with bronchopneumonia, and the younger one is 7 months old with normal mentality. The mother looks broad, stocky, and tall

Bilateral iris, choroid, optic nerve colobomas and retinal detachment in an Egyptian patient with mild Baraitser-Winter syndrome

Baraitser-Winter syndrome [BRWS] is a malformation syndrome, characterized by facial dysmorphism, ocular colobomata, pachygyria, and intellectual defects. A 3.5 year old female child with BRWS has bilateral congenital ptosis, microcor-nea, iris, choroid, and optic nerve coloboma, retinal detachment, and mental retardation. She has also frontal bossing, prominent forehead, thick eyebrows, transverse slanting, hypertelorism, wide palpebral fissures, and nystagmus. The nose is broad, and bulbous with wide nares, and broad nasal tip. She has also low set posteriorly rotated ears, full cheeks, long philtrum, large mouth [macrostomia], gum hypertrophy, decayed teeth, high arched palate, pointed chin, short neck, low posterior hair line, partial left simian crease, and short fingers. MRI brain shows frontal poly-microgyria. This patient represents a mild case of Baraitser-Winter syndrome

Cornelia-de Lange syndrome in an Egyptian infant with unusual bone deformities

We report a 4 month old female infant with the typical features of Cornelia-de Lange syndrome. What was striking in our patient was the presence of skeletal anomalies not reported previously. These included arachriodactly of both fingers and toes, flexion of thumbs at metacarpoph alengeal joints, bilateral short big toes, angulation of the lower part of the bones of right forearm and both legs with multiple skin folds. Also biochemical and X-ray evidence of rickets was detected mostly due to malnutrition and failure to thrive. The patient died at the age of 5 months with bron chopneumonia and gastroenteritis

Consanguinity and its relevance to clinical genetics

Consanguineous marriages have been practiced since the early existence of modern humans. Until now, consanguinity is widely practiced in several global communities with variable rates. The present study was undertaken to analyze the effect of consanguinity on different types of genetic diseases and child morbidity and mortality. Patients were grouped according to the types of genetic errors into four groups: Group I: Chromosomal and microdeletion syndromes. Group II: Single gene disorders. Group III: Multifactorial disorders. Group IV: Diseases of different etiologies. Consanguineous marriage was highly significant in 54.4% of the studied group compared to 35.3% in the control group [P < 0.05]. Consanguineous marriages were represented in 31.4%, 7.1%, 0.8%, 6%, 9.1% among first cousins, one and a half cousins, double first cousins, second cousins and remote relatives respectively in the studied group. Comparison between genetic diseases with different modes of inheritance showed that recessive and multifactorial disorders had the highest values of consanguinity [78.8%, 69.8%, respectively], while chromosomal disorders had the lowest one [29.1%]. Consanguineous marriage was recorded in 51.5% of our cases with autosomal dominant diseases and in 31% of cases with X linked diseases, all cases of mental retardation [100%] and in 92.6% of patients with limb anomalies [P < 0.001]. Stillbirths, child deaths and recurrent abortions were significantly increased among consanguineous parents [80.6%, 80%, 67%] respectively than among non consanguineous parents. In conclusion, consanguineous marriage is significantly higher in many genetic diseases which suggests that couples may have deleterious lethal genes, inherited from common ancestor and when transmitted to their offsprings, they can lead to prenatal, neonatal, child morbidity or mortality. So public health education and genetic counseling are highly recommended in our community

Oral-facial-digital syndrome type II: transitional type between mohr and varadi

We report a 2 months old boy, the first in order of birth of non-consanguineous parents, with several typical features of oral-facial-digital syndrome type II [OFDS II] including cleft lip, high arched palate, retromicrognathia, preaxial polysyndactyly of hands and feet, duplication of thumb and hallux. Interestingly, the patient also had mesoaxial polydactyly of the left hand with extra metacarpal bones characteristic of OFDS. VI, however mentality and MRI brain were normal. This unusual association may suggest an additional subgroup of OFDSs or a variant of OFDS II due to variable gene expression or a transitional type between OFDS II and OFDS VI

Sudden unexplained death in the young - a genetic approach to non-structural cardiac defects

Sudden unexpected death syndrome [SUDS] is the abrupt, unexpected natural death of an apparently healthy individual. In many cases, the cause of SUDS in young people is a genetic heart disorder. These disorders may be structural abnormalities, which are responsible for a large majority of cases, or arrhythmogenic abnormalities, which account for only a small minority of cases [e.g. long QT syndrome, Burgada syndrome and catecholaminergic polymorphic ventricular tachycardia]. Mutations in the genes responsible for these arrhythmogenic abnormalities as well as modes of inheritance and clinical presentations will be shortly discussed

Outcome of enzyme replacement therapy in children with Gaucher disease: the Egyptian experience

Gaucher disease is the most prevalent lysosomal storage diseases which results from inherited deficiency in the glucocerebrosidase enzyme. Three main clinical forms have been described: type I non-neuropathic, type II acute neuropathic and type III subacute neuropathic. Although it is panethnic disease, its presentation has some ethnic specific characteristics. In this work, we present specific characteristics as well as our experience in diagnosing and managing a group of Egyptian patients with this disease. The study included 48 patients with Gaucher disease attending Children's Hospital, Ain Shams University. The recombinant enzyme imiglucerase [cerezyme] was given in a dose of 60 U/kg/2 weeks. Haemoglobin, platelet count, plasma chitotriosidase, and abdominal ultrasound were assessed before starting therapy and every 6 months. Molecular analysis was done to 23 patients. At presentation, the mean age was 3.54 +/- 3.8 years. Ten patients [20.8%] had type I, 6 had type II [12.5%] and 26 had type III Gaucher disease [66.7%]. The commonest genotype was homozygous L444P which was present in 13 patients [56.5%] followed by homozygous N370S; found in three patients [13.04%]. Follow up after enzyme replacement therapy revealed a significant increase in weight and height, haemoglobin level and platelet count and slow reduction in the liver span and spleen length. Bone manifestations showed slow but complete improvement while neurological and respiratory manifestations were partially ameliorated with individual variations. To conclude, since most of Egyptian children with GD have type III disease and L444P/L444P genotype, a minimum dose of 60 U/kg/2 weeks should be maintained until adulthood. Higher doses started at an early age may delay the progression of neurological symptoms. Pulmonary involvement is not rare in Egyptian patients and may respond to dose increase or dose fractionation. Cardiovascular and renal involvement should be further studied in our population

Clinico-epidemiologic characteristics of spinal muscular atrophy among Egyptians

Spinal muscular atrophy [SMA] is characterized by progressive hypotonia and muscular weakness because of progressive degeneration of alpha motor neuron from anterior horn cells in the spinal cord. It is inherited by an autosomal recessive pattern. The precise frequency of SMA in Egypt has not been determined. We tried to estimate the frequency, clinical and molecular characteristics of SMAin Egypt. The study included all patients withSMAattended the Pediatric Hospital, Ain-Shams University during the period [year 1966-2009]. The study included 117 patients with SMA out of 660,280 patients attending the Pediatric Hospital. Patients selection was based on clinical examination, CPK, EMG, nerve conduction velocity, histopathology and molecular diagnosis. Frequency of SMA was 17.7/100,000, which is considered high. Type I was the commonest type [60.6%], followed by type II [26.79%], and type III [8.8%]. Consanguinity was reported in 45.5 and family history in 47.8% of patients. Molecular study was done and 54.5% of patients [types I and II] have homozygous deletion of exon 7, 36.3% of whom had also homozygous deletion of exon 8 of SMN1gene which is considered lower than that reported in other countries. SMA is more prevalent in Egypt than in many other countries. Forty-five percent of patients were chromosome 5-unlinked. We should continue to search for other mutation in Egypt to facilitate detection of carriers and prenatal diagnosis

Screening for subtle chromosomal rearrangements in an Egyptian sample of children with unexplained mental retardation

Mental retardation is present in about 1-3% of individuals in the general population, but it can be explained in about half of the cases. A descriptive study was carried out to screen for subtle chromosomal rearrangements in a group of Egyptian children with idiopathic mental retardation [IMR] to estimate its frequency if detected. The study enrolled 30 patients with IMR, with the perquisite criteria of being <18 years at referral, their IQ <70, and manifesting at least one of the criteria for selection of patients with subtelomeric abnormalities. Males were 63.3% and females were 36.7%, with a mean age of 7.08 +/- 4.22 years. Full history taking, thorough clinical examination, IQ, visual, and audiological assessment, brain CT scan, plasma aminogram, pelvi-abdominal ultrasonography, echocardiography, and cytogenetic evaluation using routine conventional karyotyping, high resolution banding [HRB], and fluorescent in situ hybridization [FISH] technique with appropriate probes were carried out for all studied patients. All enrolled patients had apparently normal karyotypes within 450 bands resolution, except for one patient who had 46, XY, [del [18] [p11.2]]. HRB and FISH showed subtle chromosomal rearrangement in 10% of cases that have been proven to be subtelomeric in 2 cases, i.e., 6.8%: 46, XY, dup [17] [p13.3], 46, XY, del [2] [q36.1-36.3], and non-subtelomeric in one case, 5.5%, 46, XX, ins [7;?] [q22;?]. To conclude, in children with IMR and clinical phenotype indicative of a suspected chromosomal anomaly, once recognizable syndromes have been excluded, abnormalities that include the ends of chromosomes must be searched for using HRB and subtelomeric FISH even when conventional karyotyping fails to demonstrate any abnormality

Congenital malformations prevalent among Egyptian children and associated risk factors

According to the World Health Organization the term congenital anomaly includes any morphological, functional, biochemical or molecular defects that may develop in the embryo and fetus from conception until birth, present at birth, whether detected at that time or not. Based on World Health Organization report, about 3 million fetuses and infants are born each year with major malformations. Several large population based studies place the incidence of major malformations at about 2-3% of all live births. In this study we tried to assess the frequency and nature of congenital malformations [CMs] among Egyptian infants and children as well as the associated maternal, paternal and neonatal risk factors. Patients [13,543] having CMs were detected among 660,280 child aged 0-18 years attending the Pediatric Hospital Ain Shams University during the period of the study [1995-2009], constituting 20/1000. Males were more affected than females [1.8:1]. According to ICD-10 classification of congenital malformations the commonest system involved were, nervous system, followed by chromosomal abnormalities, genital organs, urinary system, musculoskeletal, circulatory system, eye, ear, face, and neck, other congenital anomalies, digestive system, cleft lip and palate, and respiratory anomalies. Among the maternal risk factors detected were multiparity, age of the mother at conception, maternal illness, exposure to pollutants, and intake of the drugs in first months. Consanguineous marriage was detected in 45.8% of patients. Surveys of CMs must be done in every country to provide prevalence, pattern of occurrence, nature, identify causes, and associated risk factors to prevent or reduce the occurrence of CMs