Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a boy with truncus arteriosus, dysmorphic features, developmental delay, passing hypotonia, short segment Hirschsprung disease (HSCR), and paroxysmal hypoventilation. FISH analysis showed an interstitial deletion in chromosome band 22q11.2 coinciding with the deletions found in DiGeorge syndrome and velocardiofacial syndrome. Mutation scanning of RET, GDNF, EDNRB, and EDN3, genes associated with Hirschsprung disease, showed no aberrations. Since we know of two more patients with velocardiofacial syndrome and HSCR, we hypothesise that a gene responsible for proper development of the enteric nervous system may be included in the 22q11.2 region.
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PMID:A Hirschsprung disease locus at 22q11? 1020 49

We observed a novel 3.5 Mb 5q subtelomeric deletion in a 3-year-old girl with developmental delay, hypotonia and multiple minor anomalies. Comparison of her phenotype with the few published patients with terminal 5q35 deletions revealed several overlapping features, but also showed remarkable differences such as shortness of stature versus macrosomia. After the report of 5q35.3 microdeletions in Sotos syndrome we integrated the published BACs into the public draft sequence and exactly mapped the deletion size in our patient by FISH analysis with 15 BAC probes. We demonstrated that the deletion in our patient is immediately adjacent to the reported Sotos syndrome deletion site. Subtracting the symptoms of Sotos syndrome from the published patients with larger 5q35.3 deletions allowed us to delineate a distinct phenotype of prenatal lymphedema with increased nuchal translucency, pronounced muscular hypotonia and delay of reaching motor milestones, but speech development within normal limits, wide fontanels, failure to thrive with postnatal short stature, and multiple minor anomalies such as mildly bell-shaped chest, minor congenital heart disease, and a distinct facial gestalt, associated with the novel 3.5 Mb cryptic deletion. We further showed in our patient that the deletion of the LCT(4) synthase gene results in a reduction of cysteinyl leukotriene synthesis to about 65% compared to normal values. The prenatal nuchal lymphedema associated with this deletion syndrome my be related to the deletion of the FLT4 gene causing autosomal dominant primary lymphedema and contributes to the differential diagnosis of increased fetal nuchal translucency.
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PMID:A novel 5q35.3 subtelomeric deletion syndrome. 1290 Aug 93

Cardio-facio-cutaneous syndrome (CFC) is a sporadic, complex developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, growth deficiency, hypotonia, and developmental delay. CFC is caused by alteration of activity through the mitogen-activated protein kinase (MAPK) pathway due to heterogeneous de novo germline mutations in B-Raf mutant proteins, MEK1 and MEK2. Approximately 75% of individuals with CFC have mutations in BRAF. In vitro functional studies demonstrate that many of these mutations confer increase activity upon the mutant protein as compared to the wildtype protein. However, as is seen cancer, some of the B-Raf mutant proteins are kinase impaired. Western blot analyses corroborate kinase assays as determined by mutant proteins phosphorylating downstream effectors MEK and ERK. Approximately 25% of individuals with CFC have mutations in either MEK1 or MEK2 that lead to increased MEK kinase activity as judged by increased phosphorylation of its downstream effector ERK. Unlike BRAF, no somatic mutations have ever been identified in MEK genes. The identification of novel germline BRAF and MEK mutations in CFC will help understand the pathophysiology of this syndrome. Furthermore, it will also provide insight to the normal function of B-Raf and MEK, and contribute to the knowledge of the role of the MAPK pathway in cancer. Since the MAPK pathway has been studied intensively in the context of cancer, numerous therapeutics that specifically target this pathway may merit investigation in this population of patients.
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PMID:Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. 1841 55

We report on a 6-month-old boy with craniosynostosis, pseudohypoparathyroidism type 1a (PHP1A), and a GNAS gene mutation. He had synostoses of the coronal, frontal, and sagittal sutures, brachyturricephaly, and hydrocephaly. He also had congenital hypothyroidism, round face, full cheeks, shortness of limbs, mild developmental delay, and muscular hypotonia. Because of progressive hydrocephaly, the synostosis was corrected surgically but circulatory decompensation led to disseminated intravascular coagulation and cerebral infarctions. Our patient died 8 days later. Postmortem molecular studies of GNAS, the gene for guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (gene for PHP1A), identified a de novo heterozygous 3 bp in frame deletion predicting a deletion of the asparagine residue at position 377 (deltaN377). This is the second report of this mutation. Results of molecular studies of craniosynostosis genes (FGFR2, FGFR3) and of numerous genetic variants predisposing to bleeding disorders were normal. We question whether craniosynostosis and trauma-induced bleeding disorder may be manifestations of PHP1A, or if our patient had two or three different congenital disorders.
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PMID:Boy with pseudohypoparathyroidism type 1a caused by GNAS gene mutation (deltaN377), Crouzon-like craniosynostosis, and severe trauma-induced bleeding. 1953 Jan 87

Sotos syndrome (MIM #117550) is an autosomal dominant condition characterized by pre and postnatal overgrowth, macrocephaly and typical facial gestalt with frontal bossing, hypertelorism, antimongoloid slant of the palpebral fissures, prominent jaw and high and narrow palate. This syndrome is also frequently associated with brain, cardiovascular, and urinary anomalies and is occasionally accompanied by malignant lesions such as Wilms tumour and hepatocarcinoma. The syndrome is known to be caused by mutations or deletions of the NSD1 gene. To detect both 5q35 microdeletions and partial NSD1 gene deletions we screened 30 Brazilian patients with clinical diagnosis of Sotos syndrome by multiplex ligation dependent probe amplification. We identified one patient with a total deletion of NSD1 and neighbouring FGFR4, other with missing NSD1 exons 13-14 and another with a deletion involving FGFR4 and spanning up to NSD1 exon 17. All deletions were de novo. The two NSD1 partial deletions have not been previously reported. The clinical features of the three patients included a typical facial gestalt with frontal bossing, prominent jaw and high anterior hairline; macrocephaly, dolichocephaly, large hands; neonatal hypotonia and jaundice. All presented normal growth at birth but postnatal overgrowth. Two patients with NSD1 and FGFR4 gene deletions presented congenital heart anomalies.
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PMID:MLPA analysis in 30 Sotos syndrome patients revealed one total NSD1 deletion and two partial deletions not previously reported. 1959 67

Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a very rare autosomal recessive disorder characterized by recurrent episodes of unexplained fever, extensive anhidrosis, total insensitivity to pain, hypotonia, and mental retardation. The absence of urticarial reaction to intradermal injection of histamine is a sign of great diagnostic value, but this is common to all types of HSAN. The most frequent complications of this disease are corneal scarring, multiple fractures, joint deformities, osteomyelitis, and disabling self-mutilations. Malignant hyperthermia and sepsis are major causes of mortality. We relate the first observations of two Tunisian children with genetically confirmed HSAN IV. Our goal is to review the clinical aspects of this mysterious neuropathy and to emphasize the peculiarities of its management. These two patients are brothers from 1st-degree consanguineous parents (cousins) with no particular medical history. The 1st patient, the family's 1st child, presented in the 1st h of life with hypotonia and persistent fever, which was refractory to antipyretics. At the age of 8 months, the patient presented recurrent febrile seizures and developed significant self-mutilations of the fingers and tongue. He died 3 months later in a context of multivisceral failure from sepsis and malignant hyperthermia. The 2nd patient, currently aged 4 years, was born after a normal sister. He consulted in the neonatal period for a high fever. The diagnosis of HSAN IV was rapidly suspected and genetically confirmed. In fact, this patient is homozygous for the NTRK1 gene, whereas his sister and both parents are heterozygous. Special predispositions have been taken to improve the course of the disease such as air conditioning to control hyperthermia, a dental tray to reduce the injuries resulting from self-mutilation, regular moistening of the eyes to avoid corneal drying, and chlorpromazine to control hyperactivity and reduce injuries. The good progression with all these predispositions and others underlines the importance of appropriate multidisciplinary management and close monitoring of patients suffering from HSAN IV, especially during the first 3 years of life. Indeed, mortality, behavioral disorders, and mental retardation significantly decrease after this age. New curative treatments are expected in the next decade.
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PMID:[Hereditary sensory and autonomic neuropathy type IV: a report on two cases]. 2139 70

Obesity is a major threat to public health worldwide, and there is now mounting evidence favoring a role for the central nervous system (CNS) in weight control. A causal relationship has been recognized in both monogenic (e.g., BDNF, TRKB, and SIM1 deficiencies) and syndromic forms of obesity [e.g., Prader-Willi syndrome (PWS)]. Syndromic obesity arising from chromosomal abnormalities, that typically also affect learning and development, are often associated with congenital malformations and behavioral characteristics. We report on nine unrelated patients with a diagnosis of learning disability and/or developmental delay (DD) in addition to obesity that were found to have copy number variants (CNVs) by single nucleotide polymorphism array-based analysis. Each patient also had a distinct and complex phenotype, and most had hypotonia and other neuroendocrine issues, such as hyperphagia and hypogonadism. Molecular and clinical characterization of these patients enabled us to determine with confidence that the CNVs we observed were pathogenic or likely to be pathogenic. Overall, the CNVs reported here encompassed a candidate gene or region (e.g., SIM1) that has been reported in patients associating obesity and DD and/or intellectual disability (ID) and novel candidate genes and regions.
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PMID:Obesity with associated developmental delay and/or learning disability in patients exhibiting additional features: report of novel pathogenic copy number variants. 2340 28