Wide Variability Of Clinical Expression Research Articles

Family case of Potocki-Lupski syndrome

BackgroundPotocki-Lupski syndrome (PTLS, OMIM # 610883) is a rare genetic developmental disorder resulting from a partial heterozygous microduplication at chromosome 17p11.2. The condition is characterized by a wide variability of clinical expression, which can make its clinical and molecular diagnosis challenging.Case presentationWe report here a family (mother and her two children) diagnosed with PTLS. When examining children, neurological and psychological (neuropsychiatric) manifestations (speech delay, mild mental retardation), motor disorders, craniofacial dysmorphism (microcephaly, dolichocephaly, triangular face, wide bulging forehead, long chin, antimongoloid slant, "elfin" ears) were revealed. The suspected clinical diagnosis was confirmed by MLPA and CMA molecular genetic testing which revealed the presence of a segmental aneusomy; microduplication in the 17p11.2 region.ConclusionsChildren with PTLS can have a clinically recognizable and specific phenotype: craniofacial dysmorphism, motor and neurological manifestations, which may implicate a possible genetic disease to the attending physician. Moreover, each child with this syndrome is unique and may have a different clinical picture. The management of such patients requires a multidisciplinary team approach, including medical genetic counseling.

P-025: ABNORMAL MITOCHONDRIA RETENTION IN MATURE RED BLOOD CELLS OCCURS NOT ONLY IN SS BUT ALSO SC PATIENTS AND IS ASSOCIATED WITH HEMOLYTIC MARKERS

Purpose: Sickle cell disease (SCD), the most frequent genetic disease worldwide, results from a unique point mutation leading to the synthesis of the abnormal hemoglobin S (HbS). Under hypoxic condition, HbS polymerization causes a mechanical distortion of red blood cells (RBCs) called sickling, which is accompanied by a decrease of their deformability and their life span. SCD is characterized by a wide variability of clinical expression and a complex pathophysiology including vaso-occlusive processes, intravascular hemolysis as well as pro-inflammation, pro-coagulant and vaso-constrictive states. Recently, the abnormal mitochondria retention in mature RBCs has been documented in small series of SS patients but the biological consequences of this abnormality have not been fully documented and not been documented in other sickle cell syndromes. In the present study, we analyzed mature RBC mitochondria retention in both SS and SC patients, the second most frequent sickle cell syndrome, taking into account the biological/clinical features associated with these abnormal RBCs. Materials and methods: Eighty-nine adult SCD patients were included: 35 SS patients treated with hydroxyurea (HU), 15 SS patients not treated with HU and 39 SC patients. All of them were at steady-state and regularly followed by the sickle center of Guadeloupe. Twenty-one Guadeloupean adult controls (AA) were also included. Mature RBCs containing mitochondria were identified by flow cytometry using MitoTracker® probe as well as thiazole orange and anti-CD71 antibody to discriminate total and stress reticulocytes respectively. Correlations between the percentage of mature mitochondria+-RBCs and the following parameters were then analyzed: RBC deformability (Ektacytometry), reticulocytes (both total and CD71+) counts and levels of hemoglobin, total bilirubin, aminotransferase aspartate and lactate dehydrogenase levels using routine procedures. The impact of splenic function was evaluated using Howell-Jolly bodies, assessed by classic May-Grünwald Giemsa smears, as a marker of splenic dysfunction. We also analyzed the relationships between mitochondria+-RBCs and HU treatment as well as the rates of hyper vaso-occlusive (painful vaso-occlusion, acute chest syndrome, osteonecrosis) and hyper hemolytic (micro/macro-albuminuria, leg ulcer) complications. Results: Abnormal mitochondria+ RBCs were detected not only in SS but also in SC patients, although at a less extend. In both sickle cell syndromes, positive correlations with mitochondria+ RBCs were detected with hemolysis markers (percentage of total and stress reticulocytes). In addition, a negative relationship with hemoglobin level was detected in SS patients. A negative correlation was also detected between these abnormal mitochondria+ RBCs and RBC deformability. In contrast, no association between the presence of this RBC sub-population and clinical manifestations, hydroxyurea treatment or Howell-Jolly bodies was detected. Conclusion: In the present report, we demonstrated that abnormal retention of mitochondria in mature RBCs occurred not only in SS but also in SC patients. We also presented evidence that this phenotype could be related to hemolysis rate. Further studies are warranted to reveal the molecular mechanisms involved. E. BERNIT declares a conflict of interest: Consultancy, Expert: for NOVARTIS PHARMA SAS

Syndrome néphrogénique d’antidiurèse inappropriée : un diagnostic précoce évite les complications d’une hyponatrémie sévère

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare disease characterized by a kidney disability to dilute urine and, as a result, severe recurrent hyponatremia. Due to wide variability in clinical expression, the diagnosis still remains a challenge for clinicians. We report our experience of a case in which NSIAD was diagnosed early. We also stress the importance of early diagnosis and treatment, which protects an infant with NSAID from severe hyponatremia. A 1-month-old boy was referred to our hospital for persistent hyponatremia and intense vomiting. He was born full term after a normal pregnancy with a normal birth weight. The parents were healthy, nonconsanguineous, of Moroccan origin. They already had healthy twin girls. The physical examination was normal upon admission with no signs of dehydration and normal weight gain since birth. Plasma sodium was very low (125mmol/L) associated with low plasma urea (5mg/dL), osmolality (258 mOsm/kg) and low natriuresis (59mmol/L). These laboratory results suggested inappropriate antidiuretic hormone secretion (SIAD) and the infant was consequently treated with oral urea (he was already receiving sodium supplements that were later stopped). Due to exclusive breastfeeding, water restriction was impossible. Further biological investigation revealed undetectable plasma arginine vasopressin (AVP), suggesting the diagnosis of NSIAD. This was confirmed by genetic sequencing of the AVP receptor (AVPR2), demonstrating the presence of an R137C mutation. We herein report a case of a genetic fluid balance disorder due to an activating mutation of AVPR2. NSIAD is an X-linked disease, first described in 2005 by Feldman et al., which involved severe recurrent hyponatremia. The very early diagnosis (at 7 weeks of life) and appropriate treatment with urea prevented seizures and cerebral damage due to severe recurrent hyponatremia. Clinicians should consider the diagnosis of NSIAD in infants with recurrent hyponatremia with hemodilution and low AVP serum level. Genetic analysis of the AVPR2 sequence on the X chromosome will confirm the diagnosis and, given the wide variability of clinical expression, sequencing of the family members should be done.

Trichorhinophalangeal Syndrome Type I: A Patient with Two Novel and Different Mutations in the TRPS1 Gene

Background. Trichorhinophalangeal syndrome (TRPS) is an autosomal dominant skeletal dysplasia caused by defects involving the TRPS1 gene. Three types (TRPSs I, II, and III) have been described, exhibiting the common triad of hair, craniofacial, and skeletal abnormalities. TRPS II includes the additional characteristics of mental retardation and multiple exostoses. Case Report. We describe a sporadic case of TRPS type I in a child with two novel nonsense pathogenic mutations in the TRPS1 gene, both in heterozygosity—c.1198C>T (p. Gln400X) and c.2086C>T (p.Arg696X). None of these mutations were found in her parents. Clinical presentation included typical hair and facial features, as well as slight skeletal abnormalities. Discussion. There is a wide variability in clinical expression of TRPS I. Manifestations of the disease can be subtle, yet skeletal anomalies imply that TRPS I is more than an esthetic problem. Clinical and genetic diagnosis allows adequate followup and timely therapeutic procedures. When a single mutation was sufficient for the onset of the disease, our patient presented two different ones.

Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive cardiomyopathy showing a wide clinical spectrum in terms of clinical expressions and prognoses. This study sought to estimate the occurrence of compound and double heterozygotes for mutations in desmosomal proteins encoding genes in a cohort of ARVC/D Italian index cases, and to assess the clinical phenotype of mutations carriers. Fourty-two consecutive ARVC/D index cases who fulfilled the International Task Force diagnostic criteria were screened for mutations in PKP2, DSP, DSG2, DSC2, and JUP genes by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing. Three probands (7.1%) showing a family history of sudden death carried multiple mutations. Family screening identified an additional 7 multiple-mutation carriers. Among the 7 double heterozygotes for mutations in different genes, 2 were clinically unaffected, 2 were affected, and 3 showed some clinical signs of ARVC/D even if they did not fulfill the diagnostic criteria. Two compound heterozygotes for mutations in the same gene and 1 subject carrying 3 different mutations showed a severe form of the disease with heart failure onset at a young age. Moreover, multiple-mutation carriers showed a higher prevalence of left ventricular involvement (P = .025) than single-mutation carriers. Occurrence of compound and double heterozygotes in ARVC/D index cases is particularly relevant to mutation screening strategy and to genetic counseling. Even if multiple-mutation carriers show a wide variability in clinical expression, the extent of the disease is higher compared to that in single-mutation carriers.

Fabry disease: enzyme replacement therapy

Fabry disease is a multisystem disorder associated with wide variability in clinical expression. Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A. The enzyme defect leads to the systemic accumulation of glycosphingolipids with alpha-galactosyl moieties consisting predominantly of globotriaosylceramide, galabiosylceramide and two additional glycosphingolipids. Four hemizygotes patients with a family history of Fabry disease and deficiency of the enzyme alpha-galactosidase A were selected. Each patient received purified alpha-galactosidase by intravenous infusion (0.2 mg/kg). The infusion was administered every 2 weeks, for 40 min, for a total of 12 months. Outcome measures include neurological manifestations (acroparaesthesia, hypohidrosis, vasomotion), kidney function, cardiac manifestations, angiokeratomas, and corneal dystrophy. alpha-Galactosidase A prepared from human fibroblast is safe and well tolerated. After 12 months of therapy the mean creatinine clearance increased, there was significant improvement in the acroparaesthesias and in the hypohidrosis. Physical stigmata, such as angiokeratomas in the skin, and characteristic benign corneal abnormalities remained stable. Enzyme replacement therapy would therefore represent a significant advance in treatment of patients with Fabry disease. Enzyme replacement therapy is safe and likely to improve the prognosis of Fabry disease.

Klinefelter syndrome.

Klinefelter syndrome is the most common sex chromosome disorder. Affected males carry an additional X chromosome, which results in male hypogonadism, androgen deficiency, and impaired spermatogenesis. Some patients may exhibit all of the classic signs of this disorder, including gynecomastia, small testes, sparse body hair, tallness, and infertility, whereas others, because of the wide variability in clinical expression, lack many of these features. Treatment consists of testosterone replacement therapy to correct the androgen deficiency and to provide patients with appropriate virilization. This therapy also has positive effects on mood and self-esteem and has been shown to protect against osteoporosis, although it will not reverse infertility. Although the diagnosis of Klinefelter syndrome is now made definitively using chromosomal karyotyping, revealing in most instances a 47,XXY genotype, the diagnosis also can be made using a careful history and results of a physical examination, with the hallmark being small, firm testes. As it affects 1 in 500 male patients and presents with a variety of clinical features, primary care physicians should be familiar with this condition.

The molecular basis for disease variability in cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The disease is characterized by a wide variability of clinical expression. The cloning of the CFTR gene and the identification of its mutations has promoted extensive research into the association between genotype and phenotype. Several studies showed that there are mutations, like the delta F508 (the most common mutation worldwide), which are associated with a severe phenotype and there are mutations associated with a milder phenotype. However, there is a substantial variability in disease expression among patients carrying the same mutation. This variability involves also the severity of lung disease. Furthermore, increased frequencies of mutations are found among patients with incomplete CF expression which includes male infertility due to congenital bilateral absence of the vas deferens. In vitro studies of the CFTR function suggested that different mutations cause different defects in protein production and function. The mechanisms by which mutations disrupt CFTR function are defective protein production, processing, channel regulation, and conductance. In addition, reduced levels of the normal CFTR mRNA are associated with the CF disease. These mutations are associated with a highly variable phenotype from healthy individuals or infertile males to a typical CF disease. This variability in disease expression is associated with different levels of normally spliced transcripts. Further understanding the mechanisms of CFTR dysfunction may suggest different therapeutic strategies for each class of mutations.

The relationship between genotype and phenotype in cystic fibrosis.

Cystic fibrosis is characterized by a wide variability of clinical expression. The cloning of the cystic fibrosis transmembrane conductance regulator gene and the identification of its mutations has promoted extensive research into the association between genotype and phenotype. Several studies showed that there are mutations, such as delta F508 (the most common mutation worldwide), that are associated with a severe phenotype: early age at diagnosis, pancreatic insufficiency, poor nutritional status, high incidence of meconium ileus, and high sweat chloride levels; lung disease, however, is variable. The milder mutation is dominant over the severe mutation causing a milder phenotype. In vitro studies of cystic fibrosis transmembrane conductance regulator function suggested that different mutations cause different defects of protein production and function. Five mechanisms by which mutations disrupt cystic fibrosis transmembrane conductance regulator function have been suggested: class I mutations cause defective protein production, class II mutations are associated with defective protein processing, class III mutations are associated with defective regulation, class IV mutations are associated with defective conductance, and class V mutations include mutations affecting the level of normal messenger RNA transcript and protein required for normal function. This class might include mutations affecting correct splicing of pre-messenger RNA transcripts by either exon skipping or by inclusion of extra cryptic exons.

Studies in porphyria: VIII. Relationship of the 5α-reductive metabolism of steroid hormones to clinical expression of the genetic defect in acute intermittent porphyria

Acute intermittent porphyria (AIP) is a hereditary disease characterized biochemically by a defect in the heme pathway enzyme uroporphyrinogen I synthase (UROS) such that its activity is reduced to approximately 50 per cent of normal in all subjects who inherit the disorder. The UROS defect is transmitted in an autosomal dominant fashion, occurs in the liver as well as in other tissues, and appears not to vary with disease activity. There is wide variability in clinical expression of AIP, and the disorder remains latent in most UROS-deficient subjects. The natural history of the disease suggests a significant relationship between endocrine influences and full clinical expression of the disease after puberty. In exploring the interactions of endocrine and genetic factors in this disorder we previously found a substantial deficiency in the hepatic 5α-reductive transformation of steroid hormones in patients with clinically expressed AIP. In the present study utilizing radiolabeled hormone tracers we examined the relationship between this defect in steroid metabolism and clinical expression of the disorder in a large group of subjects including 39 UROS-deficient subjects with either clinically expressed AIP (21 subjects) or clinically latent porphyria (18 UROS-deficient subjects who had never had symptoms of AIP) and 20 normal controls. We found ratios of 5β to 5α metabolites of [4- 14C]testosterone to be substantially higher in the group with clinically expressed AIP (3.4 ± 0.5 mean ± standard error [SE], range 1.1 to 9.0) as compared with the group with latent AIP (1.0 ± 0.1, range 0.5 to 2.3) or the normal controls (1.1 ± 0.1, range 0.5 to 2.0), indicating a deficient 5α-reduction of the hormone only in the group with expressed AIP. Similarly the per cent 5α-metabolism of the adrenal hormone [1,2- 3H]11-hydroxyandrostenedione was significantly lower in those with expressed AIP (46 ± 3.6 per cent) as compared with those with latent AIP (71 ± 2.4 per cent) or normal subjects (73 ± 2.3 per cent). Erythrocyte UROS activity was not different in those with clinically latent and expressed AIP in keeping with previous findings. Thus, although the groups with expressed and latent AIP were homogeneous with respect to the extent of erythrocyte UROS deficiency, impaired 5α-reduction of steroid hormones was found only in the group with a history of clinical expression of the disorder. The reason for the defect in 5α-reduction of steroid hormones in expressed AIP is not known, but its presence supports the view that in some patients, subtle endocrine abnormalities are involved in clinical expression of the genetic defect in AIP.