phenylephrine-hydrochloride and Growth-Disorders

Exocrine pancreatic insufficiency in children can lead to lifelong complications related to malnutrition and poor growth. The clinical presentation can be subtle in the early stages of insufficiency as the large functional capacity of the pancreas is gradually lost. The pediatrician plays a crucial role in the early identification of these children to ensure a timely referral so that a diagnosis can be made and therapy initiated. Early nutritional therapy allows for prevention and correction of deficiencies, which leads to improved outcomes and survival. When insufficiency is suspected, the workup should start with an indirect test of exocrine pancreatic function, such as fecal elastase, to establish the diagnosis. Once a diagnosis is established, further testing to delineate the etiology should be pursued, with cystic fibrosis being high on the differential list and assessed for with a sweat test. Assessment of anthropometry at every visit is key, as is monitoring of laboratory parameters and physical examination findings that are suggestive of malabsorption and malnutrition. The mainstay of management is administration of exogenous pancreatic enzymes to facilitate digestion and absorption. [Pediatr Ann. 2019;48(11):e441-e447.].

Topics: Acyl-CoA Dehydrogenase, Long-Chain; Anus, Imperforate; Child; Child Nutrition Disorders; Chymotrypsin; Congenital Bone Marrow Failure Syndromes; Cystic Fibrosis; Dietary Fats; Ectodermal Dysplasia; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Feces; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Lipid Metabolism, Inborn Errors; Mitochondrial Diseases; Muscular Diseases; Nose; Nutrition Assessment; Pancreas; Pancreatic Diseases; Pancreatic Elastase; Pancreatic Function Tests; Pancreatitis, Chronic; Shwachman-Diamond Syndrome; Steatorrhea; Trypsinogen

Johanson-Blizzard syndrome (JBS) is considered as an infrequent, but clinically easily recognizable autosomal recessive entity by the pathognomonic combination of congenital exocrine pancreatic insufficiency and hypoplastic alae nasi, in addition to other distinctive findings such as scalp defects, hypothyroidism, and rectourogenital malformations. There are few reports of patients with JBS in association with facial clefting, referring all to types 2 to 6 of Tessier's classification that can be characterized properly as oblique facial clefts (OFCs). We describe the clinical aspects in four patients with JBS and extensive OFCs. In all of them, the diagnosis of JBS was confirmed by the demonstration of homozygous or compound-heterozygous mutations in the UBR1 gene. Additionally, we review three previously reported cases of JBS with OFCs. Taking into account a number of approximately 100 individuals affected by JBS that have been published in the literature we estimate that the frequency of OFCs in JBS is between 5% and 10%. This report emphasizes that extensive OFCs may be the severe end of the spectrum of facial malformations occurring in JBS. No obvious genotype phenotype correlation could be identified within this cohort. Thus, UBR1 should be included within the list of contributory genes of OFCs, although the exact mechanism remains unknown. © 2016 Wiley Periodicals, Inc.

Topics: Alleles; Anus, Imperforate; Cleft Palate; Consanguinity; Craniofacial Dysostosis; Diagnostic Imaging; DNA Mutational Analysis; Ectodermal Dysplasia; Eye Abnormalities; Female; Genetic Association Studies; Genotype; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Infant, Newborn; Intellectual Disability; Introns; Male; Maxillofacial Abnormalities; Mutation; Nose; Pancreatic Diseases; Phenotype; Ubiquitin-Protein Ligases

The N-end rule pathway is a unique branch of the ubiquitin-proteasome system in which the determination of a protein's half-life is dependent on its N-terminal residue. The N-terminal residue serves as the degradation signal of a protein and thus called N-degron. N-degron can be recognized and modifed by several steps of post-translational modifications, such as oxidation, deamination, arginylation or acetylation, it then polyubiquitinated by the N-recognin for degradation. The molecular basis of the N-end rule pathway has been elucidated and its physiological functions have been revealed in the past 30 years. This pathway is involved in several biological aspects, including transcription, differentiation, chromosomal segregation, genome stability, apoptosis, mitochondrial quality control, cardiovascular development, neurogenesis, carcinogenesis, and spermatogenesis. Disturbance of this pathway often causes the failure of these processes, resulting in some human diseases. This review summarized the physiological functions of the N-end rule pathway, introduced the related biological processes and diseases, with an emphasis on the inner link between this pathway and certain symptoms.

Topics: Aminoacyltransferases; Animals; Anus, Imperforate; Cardiovascular System; Ectodermal Dysplasia; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Neurodegenerative Diseases; Neurogenesis; Nose; Pancreatic Diseases; Protein Processing, Post-Translational; Signal Transduction; Spermatogenesis

Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n = 29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.

Topics: Abnormalities, Multiple; Anus, Imperforate; Databases, Genetic; Dwarfism; Ectodermal Dysplasia; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Mutation; Nose; Pancreatic Diseases; Phenotype; Ubiquitin-Protein Ligases

Johanson-Blizzard syndrome is a very rare autosomal recessive disorder caused by mutations in the Ubiquitin-Protein Ligase E3 Component N-Recognin 1 (UBR1) gene. The syndrome is characterized by exocrine pancreatic insufficiency and a wide range of additional clinical features, including aplasia or hypoplasia of the alae nasi, oligodontia, sensorineural hearing loss, hypothyroidism, scalp defects, mental retardation, and developmental delay. Several other abnormalities in different organs, particularly anorectal, urogenital, and cardiac anomalies have been reported since the first description of this syndrome four decades ago. UBR1 gene defects are underlying the disease. Only symptomatic treatment is available. Exocrine pancreas insufficiency plus abnormal alae nasi is pathognomonic for Johanson-Blizzard syndrome.

Topics: Abnormalities, Multiple; Anus, Imperforate; Child; Deafness; Ectodermal Dysplasia; Eponyms; Exocrine Pancreatic Insufficiency; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Nose; Pancreatic Diseases; Ubiquitin-Protein Ligases

To study the clinical characteristics and diagnosis of the Johanson-Blizzard syndrome.. The clinical characteristics and diagnosing procedure of 1 case with Johanson-Blizzard syndrome were analyzed, and genetic analysis was made in diagnosing procedure, and 28 cases of Johanson-Blizzard syndrome with detailed clinical data were reviewed and analyzed.. A one year and nine months old girl, who was initially admitted to the hospital because of fatty diarrhea and increased frequency of defecation. Imperforate anus, and aplastic alae nasi was noticed after birth. On physical examination, short stature, mental retardation, tooth abnormalities and scalp defects were observed. Fat globule was found by routine stool test. Serum biochemistry showed an exocrine and endocrine pancreatic insufficiency, CT scan of the abdomen demonstrated fatty replacement of the pancreas, UBR1 gene analysis showed heterozygous for two missense changes. In all 29 cases, exocrine pancreatic insufficiency (72.4%) and hypoplasia of the alae nasi (93%) were the most common clinical manifestations, and sensorineural hearing loss (59%), scalp defects (69%) and hair thinning or upsweep of the hair (44.8%), hypothyroidism (44.8%), absence of permanent teeth (44.8%) and imperforate anus (21%) were also very common, but did not include consanguineous marriage of parents (10.3%).. Johanson-Blizzard syndrome is a rare autosomal recessive multisystem disorder, it is characterized by the association of congenital exocrine pancreatic insufficiency and hypoplasia or aplasia of the nasal wings, and can be diagnosed by clinical characteristics and UBR1 gene analysis.

Topics: Anus, Imperforate; Deafness; Ectodermal Dysplasia; Female; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Infant; Intellectual Disability; Nose; Pancreatic Diseases; Ubiquitin-Protein Ligases

Alopecia present from birth includes a broad differential diagnosis and often represents a diagnostic and therapeutic challenge for the involved physician.. An initial correct diagnosis and classification is essential because structural hair defects may be the expression of a genetic disorder affecting hair growth, part of a congenital syndrome with accompanying hair malformations, or a marker for an underlying metabolic disorder and may impact the mental and physical development of a child. Pathological hair loss rarely occurs in the first year of life; however, it may be a leading symptom of many congenital diseases.. In recent years, the clinical and microscopic features of hereditary hair shaft disorders have been characterized and classified. Furthermore, significant progress has been made in our knowledge of genes that control the normal development and differentiation of hair follicles, and thus the research is to define and classify the hair disorders within a genetic basis.. In this article we discuss several types of genotrichosis and provide a practical classification based on their clinical features.

Topics: Alopecia; Aneurysm; Carcinoma, Basal Cell; Child; Cleft Lip; Cleft Palate; Deafness; Ectodermal Dysplasia; Eczema; Facies; Fingers; Growth Disorders; Hair Diseases; Hallermann's Syndrome; Histiocytoma, Benign Fibrous; Humans; Hypotrichosis; Ichthyosis; Intellectual Disability; Keratitis; Langer-Giedion Syndrome; Microcephaly; Nose; Skin Diseases, Genetic; Skin Neoplasms

We present the case of a 7-month-old girl with the karyotype 46,XX, der(13) t(2;13)(p23;p11.2).ish der(13)(wcp2+) de novo. Painting confirmed that the additional segment on 13p was of chromosome 2 origin, resulting in trisomy 2p23 -->2pter. The child had a prominent forehead with a flat hemangioma, depressed nasal bridge, protruding tongue, posteriorly angulated ears, esotropia with poor abduction of the right eye, bilateral severe myopia (-5.5 D), retinal hypopigmentation, foveal hypoplasia, and striking left optic nerve hypoplasia. She also had pectus excavatum, a protruding abdomen with diastasis recti, generalized hypotonia, delayed fine and gross motor development, grade II reflux on the left side, and grade III-IV reflux on the right side. An EEG showed epileptiform discharges. Computed tomographic scan of the brain showed decreased white matter, but magnetic resonance imaging showed normal results.

Topics: Abnormalities, Multiple; Adult; Chromosome Painting; Chromosomes, Human, Pair 2; Eye Diseases; Female; Growth Disorders; Heart Diseases; Humans; Infant; Karyotyping; Male; Nose; Phenotype; Psychomotor Disorders; Trisomy

Topics: Abnormalities, Multiple; Diagnosis, Differential; Exocrine Pancreatic Insufficiency; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Nose; Prognosis; Scalp; Tooth Abnormalities

Cerebro-Oculo-Nasal syndrome; a new multiple congenital anomaly/mental retardation syndrome was first reported by Richieri-Costa and Guion-Almeida in 1993 (Am J Med Genet 47:702-706) in two patients. To the best of our knowledge four additional cases have been reported. The main features of the syndrome are anophthalmia/microphthalmia, abnormal nares, and central nervous system anomalies. In this report, an additional sporadic case of this syndrome is presented. A 6-year-old girl from a non-consanguineous couple with normal prenatal growth parameters and retarded postnatal growth had anophthalmia, uplifted right nares with skin tag, and slight clefting at the tip of the nose, upper lip and gingiva. She also had a high-arched narrow palate, slightly low set ears, hypertelorism, a CNS defect and mental retardation. Additional findings were hypoplastic teeth with dental malocclusion, muscular hypotonia and midline hyperpigmentation over the anterior neck and the abdomen.

Topics: Abnormalities, Multiple; Anophthalmos; Brain; Child; Craniofacial Abnormalities; Female; Growth Disorders; Humans; Intellectual Disability; Nose; Syndrome; Tomography, X-Ray Computed

5p- is a well-defined syndrome, but phenotypic correlations of 5q are poorly described in the literature. We present a case of a female child with interstitial deletion in the 5q13.1q15 region. Comparison of the clinical features of this patient with others reported in the literature suggests an emerging clinical syndrome defined by short stature, failure to thrive, mental retardation, slanting palpebral fissures, malformed ears, short neck and depressed nasal bridge. Based on our endocrine testing, we hypothesize that the short stature could be, in part, due to growth hormone deficiency. The recent assignment of growth hormone receptor gene to the short arm of chromosome 5 and the presence of several genes for growth factors and growth factor receptors on 5q raise interesting possibilities for the explanation of short stature in such cases.

Topics: Adult; Body Height; Child; Chromosome Deletion; Chromosomes, Human, Pair 5; Cleft Palate; Ear; Failure to Thrive; Female; Foot Deformities, Congenital; Growth Disorders; Growth Hormone; Heart Defects, Congenital; Humans; Infant, Newborn; Male; Nose; Pregnancy; Syndactyly; Syndrome

Topics: Abnormalities, Multiple; Blepharoptosis; Growth Disorders; Humans; Limb Deformities, Congenital; Nose; Syndrome

The effects of growth hormone (GH) therapy in children have yet to be completely catalogued. In the present study, the effect of high-dose GH treatment on craniofacial growth was evaluated once yearly in 21 pre-pubertal, non-GH-deficient children born small for gestational age. These children were randomly allocated to be either untreated or treated with GH at a daily subcutaneous dose of 0.2 or 0.3 IU/kg for 2 yrs. The group consisted of 12 girls and 9 boys with a mean age of 5.1 yr (range, 2 to 8 yr), bone age of 3.4 yr, and height SDS of -3.6. At the start of the study, all children showed an overall delay of craniofacial growth. This cohort of short children born small for gestational age showed a small SNB angle and a large ANB angle; all other angular measurements were within normal range. GH treatment accelerated growth in several craniofacial components, especially the posterior total facial height, the cranial base length, and the overall mandibular length. The increase of the mandibular length increased the SNB angle; no other angular measurements were affected. Age at start of treatment differently influenced the increase in posterior and total cranial base length, the increase in mandibular corpus length, and the position of the mandible in relation to the cranial base. Although GH treatment for 2 yrs led to a craniofacial growth acceleration, the position of the mandible in relation to the cranial base and the craniofacial size in lateral aspect were not normalized in the majority of the GH-treated children. No signs of disproportional growth were evidenced after 2 yrs of high-dose GH treatment. In conclusion, short pre-pubertal SGA children display an overall delay of linear craniofacial growth and a retrognathic mandible. High-dose GH treatment over 2 yrs leads to craniofacial catch-up growth, which is pronounced in regions where interstitial cartilage is involved and results in a less convex face in profile.

Topics: Age Determination by Skeleton; Age Factors; Body Height; Cephalometry; Child; Child, Preschool; Cohort Studies; Evaluation Studies as Topic; Female; Follow-Up Studies; Growth Disorders; Growth Substances; Humans; Infant, Newborn; Infant, Small for Gestational Age; Injections, Subcutaneous; Male; Mandible; Maxilla; Maxillofacial Development; Nose; Retrognathia; Skull Base; Vertical Dimension

In this paper, we have carefully investigated the clinical phenotype and genotype of patients with Johanson-Blizzard syndrome (JBS) with diabetes mellitus as the main manifestation. Retinal vessel segmentation is an important tool for the detection of many eye diseases and plays an important role in the automated screening system for retinal diseases. A segmentation algorithm based on a multiscale attentional resolution network is proposed to address the problem of insufficient segmentation of small vessels and pathological missegmentation in existing methods. The network is based on the encoder-decoder architecture, and the attention residual block is introduced in the submodule to enhance the feature propagation ability and reduce the impact of uneven illumination and low contrast on the model. The jump connection is added between the encoder and decoder, and the traditional pooling layer is removed to retain sufficient vascular detail information. Two multiscale feature fusion methods, parallel multibranch structure, and spatial pyramid pooling are used to achieve feature extraction under different sensory fields. We collected the clinical data, laboratory tests, and imaging examinations of JBS patients, extracted the genomic DNA of relevant family members, and validated them by whole-exome sequencing and Sanger sequencing. The patient had diabetes mellitus as the main manifestation, with widened eye spacing, low flat nasal root, hypoplastic nasal wing, and low hairline deformities. Genetic testing confirmed the presence of a c.4463 T > C (p.Ile1488Thr) pure missense mutation in the UBR1 gene, which was a novel mutation locus, and pathogenicity analysis indicated that the locus was pathogenic. This patient carries a new UBR1 gene c.4463 T > C pure mutation, which improves the clinical understanding of the clinical phenotypic spectrum of JBS and broadens the genetic spectrum of the UBR1 gene. The experimental results showed that the method achieved 83.26% and 82.56% F1 values on CHASEDB1 and STARE standard sets, respectively, and 83.51% and 81.20% sensitivity, respectively, and its performance was better than the current mainstream methods.

Topics: Algorithms; Anus, Imperforate; Data Mining; Diabetes Mellitus; Diabetic Retinopathy; Ectodermal Dysplasia; Fundus Oculi; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Image Processing, Computer-Assisted; Intellectual Disability; Nose; Pancreatic Diseases; Perfusion

Topics: Anus, Imperforate; Child; Ectodermal Dysplasia; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Nose; Pancreatic Diseases; Pathology, Molecular

The ubiquitin-proteasome system facilitates the degradation of unstable or damaged proteins. UBR1-7, which are members of hundreds of E3 ubiquitin ligases, recognize and regulate the half-life of specific proteins on the basis of their N-terminal sequences ("N-end rule"). In seven individuals with intellectual disability, epilepsy, ptosis, hypothyroidism, and genital anomalies, we uncovered bi-allelic variants in UBR7. Their phenotype differs significantly from that of Johanson-Blizzard syndrome (JBS), which is caused by bi-allelic variants in UBR1, notably by the presence of epilepsy and the absence of exocrine pancreatic insufficiency and hypoplasia of nasal alae. While the mechanistic etiology of JBS remains uncertain, mutation of both Ubr1 and Ubr2 in the mouse or of the C. elegans UBR5 ortholog results in Notch signaling defects. Consistent with a potential role in Notch signaling, C. elegans ubr-7 expression partially overlaps with that of ubr-5, including in neurons, as well as the distal tip cell that plays a crucial role in signaling to germline stem cells via the Notch signaling pathway. Analysis of ubr-5 and ubr-7 single mutants and double mutants revealed genetic interactions with the Notch receptor gene glp-1 that influenced development and embryo formation. Collectively, our findings further implicate the UBR protein family and the Notch signaling pathway in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism that differs from JBS. Further studies exploring a potential role in histone regulation are warranted given clinical overlap with KAT6B disorders and the interaction of UBR7 and UBR5 with histones.

Topics: Animals; Anus, Imperforate; Caenorhabditis elegans; Cell Line; Ectodermal Dysplasia; Epilepsy; Growth Disorders; Hearing Loss, Sensorineural; HEK293 Cells; Histones; Humans; Hypothyroidism; Intellectual Disability; Mice; Mutation; Neurodevelopmental Disorders; Nose; Pancreatic Diseases; Proteasome Endopeptidase Complex; Receptors, Notch; Signal Transduction; Ubiquitin-Protein Ligases

Calpainopathies constitute a heterogeneous group of disorders resulting from deficiencies in calpains, calcium-specific proteases that modulate substrates by limited proteolysis. Clinical manifestations depend on tissue-specific expression of the defective calpain and substrate specificity. CAPN15, encoding the Drosophila small optic lobes (sol) homolog, was recently found to cause various eye defects in individuals carrying bi-allelic missense variants. Here we report on two siblings with manifestations reminiscent of Johanson-Blizzard syndrome including failure to thrive, microcephaly, global developmental delay, dysmorphic features, endocrine abnormalities and congenital malformations, in addition to eye abnormalities. Exome sequencing identified a homozygous 47 base-pair deletion in a minimal intron of CAPN15, including the splice donor site. Sequencing of cDNA revealed single exon skipping, resulting in an out-of-frame deletion with a predicted premature termination codon. These findings expand the phenotypic spectrum associated with CAPN15 variants, and suggest that complete loss-of-function is associated with a recognizable syndrome of congenital malformations and developmental delay, overlapping Johanson-Blizzard syndrome and the recently observed brain defects in Capn15 knockout (KO) mice. Moreover, the data highlight the unique opportunity for indel detection in minimal introns.

Topics: Abnormalities, Multiple; Alleles; Anus, Imperforate; Base Pairing; Calpain; Codon, Nonsense; Consanguinity; Developmental Disabilities; Ectodermal Dysplasia; Eye Abnormalities; Genetic Association Studies; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; INDEL Mutation; Intellectual Disability; Introns; Male; Microphthalmos; Muscle Hypotonia; Nose; Pancreatic Diseases; Pedigree; RNA Splice Sites; Sequence Deletion; Steatorrhea

Johanson-Blizzard Syndrome (JBS) is a rare autosomal recessive genetic disorder characterized by exocrine pancreatic insufficiency, distinct abnormal facial appearance and varying degrees of growth retardation. Variants in UBR1 gene are considered to be responsible for the syndrome. Here, we describe a 3-year old boy, who visited our clinic for severe growth retardation and frequent oily diarrhea. The physical examination revealed nasal alae aplasia, scalp defect, and maldescent of left testicle. Transabdominal ultrasound and computed tomography scan of his abdomen demonstrated complete fatty replacement of the pancreas. The clinical, laboratory, and imaging findings strongly suggest the diagnosis of hereditary pancreatitis. Whole exome sequencing revealed two rare compound heterozygous variants, c.2511T > G (p.H837Q) and c.1188T > G (p.Y396X), in the UBR1 gene of this boy, so, the diagnosis of JBS was established. This is the first report of Chinese patient with JBS, and our study indicates that transabdominal ultrasound and computed tomography are two useful and noninvasive imaging methods for the diagnosis and evaluation of JBS, and identification of these two novel variants expands the database of UBR1 gene variants. Furthermore, with the availability of the identification technology for these variants, prenatal diagnosis could be offered for future pregnancies.

Topics: Adipose Tissue; Anus, Imperforate; Child, Preschool; Ectodermal Dysplasia; Exome; Gene Frequency; Growth Disorders; Hearing Loss, Sensorineural; Heterozygote; Humans; Hypothyroidism; Intellectual Disability; Male; Models, Molecular; Nose; Pancreatic Diseases; Pancreatitis; Physical Examination; Tomography, X-Ray Computed; Ubiquitin-Protein Ligases; Ultrasonography

Johanson-Blizzard Syndrome (JBS) was first described by Johanson and Blizzard. It exhibits autosomal recessive inheritance and is characterized by mutation in the UBR1 gene on the long arm of Chromosome 15. The phenotypic features as well as diarrhoea that occurs due to the exocrine pancreatic insufficiency constitute the main clinical symptoms. This article discusses Johanson-Blizzard Syndrome due to the case followed-up by us with the symptoms of deafness and diarrhoea as well as typical facial appearance.

Topics: Anus, Imperforate; Child, Preschool; Diarrhea; Ectodermal Dysplasia; Exocrine Pancreatic Insufficiency; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Infant; Intellectual Disability; Male; Nose; Pancreatic Diseases

We present a case of a child with pancreatic insufficiency and facial defects typical of Johanson-Blizzard syndrome (JBS), along with the more facultative anomalies of the JBS, such as those of the urogenital system including persistent urogenital sinus, urethral duplication and dysplastic kidneys. Fetal ultrasound in a 21-year-old G1P1 woman revealed ambiguous genitalia. Examination at birth revealed a phallic structure with urethral meatus, non-palpable gonads, two orifices in close proximity in the perineum, with the anterior being a common urogenital channel and the posterior, the rectum. A voiding cystourethrogram/genitogram showed bilateral high-grade vesicoureteral reflux and a common urogenital sinus extending 1.5 cm before dividing into three channels: the native urethra, an accessory urethra directed anteriorly towards the clitoris and a septate vagina with uterus didelphys. JBS was suspected by clinical presentation and confirmed by UBR1 molecular testing (46,XX). At 16 months of age, she underwent feminising genitoplasty and posterior sagittal anorectoplasty.

Topics: Anus, Imperforate; Diagnosis, Differential; Ectodermal Dysplasia; Female; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Infant, Newborn; Intellectual Disability; Nose; Pancreatic Diseases; Pregnancy; Ultrasonography, Prenatal; Urogenital Abnormalities; Young Adult

The N-end rule pathway controls the half-life of proteins based on their N-terminal residue. Positively charged type 1 N-degrons are recognized by a negatively charged pocket on the Zn finger named the UBR box. Here, we show that the UBR box is rigid, but bound water molecules in the pocket provide the structural plasticity required to bind different positively charged amino acids. Ultra-high-resolution crystal structures of arginine, histidine, and methylated arginine reveal that water molecules mediate the binding of N-degron peptides. Using a high-throughput binding assay and isothermal titration calorimetry, we demonstrate that the UBR box is able to bind methylated arginine and lysine peptides with high affinity and measure the preference for hydrophobic residues in the second position in the N-degron peptide. Finally, we show that the V122L mutation present in Johanson-Blizzard syndrome patients changes the specificity for the second position due to occlusion of the secondary pocket.

Topics: Anus, Imperforate; Binding Sites; Ectodermal Dysplasia; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Hypothyroidism; Intellectual Disability; Mutation, Missense; Nose; Pancreatic Diseases; Peptides; Protein Binding; Substrate Specificity; Ubiquitin-Protein Ligases; Water

Sensorineural hearing loss (SNHL) occurs in more than 80% of cases of Johanson Blizzard Syndrome (JBS). However, limited knowledge exists in medical literature of cochlear implantation (CI) outcomes in children with JBS. We report the case of a 5 year-old male with JBS and bilateral CI. While minimal progress in spoken language scores was noted after 4 years of bilateral CI use, substantial improvements in discrimination of speech sounds and audibility of spoken language and environmental sounds were documented. Cochlear implantation is an available treatment option of profound SNHL in children with JBS even if spoken language outcomes are marginal.

Topics: Anus, Imperforate; Child, Preschool; Cochlear Implantation; Cochlear Implants; Ectodermal Dysplasia; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Male; Nose; Pancreatic Diseases; Speech Perception; Treatment Outcome

Johanson-Blizzard syndrome (JBS, MIM #243800) is a very rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, nasal wing hypoplasia, hypodontia, and other abnormalities. JBS is caused by mutations of the UBR1 gene (MIM *605981), encoding a ubiquitin ligase of the N-end rule pathway.. Molecular findings in a total of 65 unrelated patients with a clinical diagnosis of JBS who were previously screened for UBR1 mutations by Sanger sequencing were reviewed and cases lacking a disease-causing UBR1 mutation on either one or both alleles were included in this study. In order to discover mutations that are not detectable by Sanger sequencing, we designed a probe set for multiplex ligation-dependent probe amplification (MLPA) analysis of the UBR1 gene and analyzed the copy number status of all 47 UBR1 exons.. Our previous studies using Sanger sequencing could detect mutations in 93.1% of 130 disease-associated UBR1 alleles. Six patients with a highly suggestive clinical diagnosis of JBS and unsolved genotype were included in this study. MLPA analysis detected six alleles harboring exon deletions/duplications, thereby raising the mutation detection rate in the entire cohort to 97.7% (127/130 alleles).. We conclude that single or multi-exon deletions or duplications account for a substantial proportion of JBS-associated UBR1 mutations.

Topics: Adult; Alleles; Anus, Imperforate; Base Sequence; Child; Child, Preschool; DNA; DNA Mutational Analysis; Ectodermal Dysplasia; Exons; Female; Gene Deletion; Gene Duplication; Genotype; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Male; Multiplex Polymerase Chain Reaction; Nose; Pancreatic Diseases; Phenotype; Ubiquitin-Protein Ligases

Johanson-Blizzard Syndrome (JBS) (MIM #243800) is a rare autosomal recessive genetic disorder characterized by exocrine pancreatic insufficiency, abnormal facial appearance and varying degrees of mental retardation. Mutations in UBR1 gene (MIM *605981) are considered to be responsible for the syndrome. Here, we report a 3 year-old mentally normal JBS girl. The patient presented with exocrine pancreatic insufficiency as well as failure-to-thrive. On dysmorphological examination, she was noted to have an abnormal hair pattern with frontal upsweep and alae nasi hypoplasia. With these findings, JBS diagnosis was established clinically. Molecular analysis of the UBR1 gene revealed two inherited novel mutations; one coming from each parent. These novel mutations were c. 1280T>G and c. 2432+5G>C, and they were found to be disease causing via in-silico analysis. In conclusion, for patients with longstanding exocrine pancreatic insufficiency, it should be considered as being symptomatic of a far broader picture. To omit connection with rare genetic diseases, such as Johanson-Blizzard Syndrome, a detailed dysmorphological examination ought to be performed.

Topics: Anus, Imperforate; Child, Preschool; DNA Mutational Analysis; Ectodermal Dysplasia; Female; Genetic Association Studies; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Mutation, Missense; Nose; Pancreatic Diseases; Phenotype; Point Mutation; Ubiquitin-Protein Ligases

Topics: Anus, Imperforate; Ectodermal Dysplasia; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Mutation; Nose; Pancreatic Diseases; Ubiquitin-Protein Ligases

Johanson-Blizzard syndrome (JBS); (OMIM: 243800) presents with features of malabsorption and dysmorphic features with onset of symptoms in infantile age group. The disorder was first described in the year 1971 with report of the first Indian case in 2004. We discuss two rare phenotypes (hepatitis and anemia) in a molecularly confirmed case of JBS.

Topics: Anemia; Anus, Imperforate; Chromosomes, Human, Pair 15; Ectodermal Dysplasia; Genes, Recessive; Genetic Testing; Genotype; Growth Disorders; Hearing Loss, Sensorineural; Hematologic Tests; Hepatitis; Humans; Hypothyroidism; Infant; Intellectual Disability; Male; Mutation; Nose; Pancreatic Diseases; Phenotype; Ubiquitin-Protein Ligases

The tricho-rhino-phalangeal syndrome type III (TRPS III) is a rare autosomal dominantly inherited condition. The main clinical features are sparse and slow-growing hair and nails, a pear-shaped nose with a bulbous tip, elongated and flat philtrum, thin upper lip, cone-shaped epiphyses of the phalanges, and short stature. All patients have a point mutation in the TRPS1 gene.. In this paper, we present a 13-year-old female with the typical clinical features of TRPS III, extreme growth retardation, severe deformities of both proximal radii resulting in limited extension of the elbows, and chronic renal failure (CRF) in addition. Molecular diagnostics revealed a missense mutation in exon 6 of TRPS1 that she inherited from her father who is also affected with TRPS III, but does not have CRF. In the index patient, the CRF was found to be due to bilateral renal hypodysplasia (RHD).. Beside the renal dysplasia, the girl had severe deformities of the proximal radii - findings which have not been reported so far in TRPS III.

Topics: Abnormalities, Multiple; Adolescent; DNA-Binding Proteins; Female; Fingers; Growth Disorders; Hair Diseases; Humans; Kidney; Kidney Failure, Chronic; Langer-Giedion Syndrome; Nose; Point Mutation; Radius; Repressor Proteins; Syndrome; Transcription Factors

Johanson-Blizzard syndrome is a rare congenital autosomal recessive disease characterized by the association of congenital deficiency of the exocrine pancreatic function and multiple malformations. One of the most common manifestations of this pathology is sensorineural hearing loss of different severity and anomalous development of the inner ear. The case of cochlear implantation in the patient presenting with bilateral sensorineural deafness, congenital malformation of the inner ear, and stenosis of the internal auditory canal is reported.

Topics: Anus, Imperforate; Child, Preschool; Cochlear Implantation; Ectodermal Dysplasia; Growth Disorders; Hearing Loss, Sensorineural; Hearing Tests; Humans; Hypothyroidism; Intellectual Disability; Male; Nose; Pancreatic Diseases; Treatment Outcome

Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive disorder resulting from loss-of-function mutations in the UBR1 gene. JBS can be easily recognized by its unique clinical presentation (including exocrine pancreatic insufficiency, hypoplasia/aplasia of the alae nasi, congenital scalp defects, sensorineural hearing loss, growth retardation, psychomotor retardation, and anal and genitourinary anomalies). The objective of this study is to report on the first familial case of gender-discordant twins presenting JBS and a novel mutation in the UBR1 gene. We also review literature describing molecularly confirmed cases of JBS. The female twin developed refractory severe diarrhea after the second month of life and died at the age of 3 months. The male twin also developed diarrhea and failure to thrive after the 3 month of life but improved when nutrition support and pancreatic enzyme replacement was started, and he has survived into adolescence. Both patients presented typical clinical features of JBS. A homozygous nonsense mutation (c.3682C>T; p.Q1228X) in UBR1 was confirmed. Severe presentation of JBS usually involves deleterious (nonsense, frameshift, or splice-site) mutations in the UBR1 gene that are thought to completely abolish the expression of a functional protein product, as in this familial case; however, milder presentation of JBS has occasionally been observed with missense mutations in at least 1 of the 2 copies of UBR1, in which there may be residual activity of the product of this gene. Early diagnosis and adequate treatment are crucial for a favorable outcome.

Topics: Adolescent; Anus, Imperforate; Codon, Nonsense; Ectodermal Dysplasia; Female; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Male; Nose; Pancreatic Diseases; Pedigree; Sequence Analysis, DNA; Ubiquitin-Protein Ligases

Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive syndrome characterized by dysmorphic nasal alae, ectodermal abnormalities, exocrine pancreatic insufficiency and early growth failure. Most patients are diagnosed by clinical criteria prenatally or in early infancy. Nonsense, frame shift and splice-site mutations of the ubiquitin ligase gene (UBR1) lead to early loss of acinar cells in individuals with JBS.. We describe a previously asymptomatic patient with ectodermal dysplasia presenting with sudden onset exocrine pancreatic insufficiency in adolescence. The family reports an identical twin brother with similar symptoms.. This case illustrates that the phenotypic variability of pancreatic involvement in JBS may be subtle and may not manifest until the second decade of life. We suspect that this mild phenotype results from mutations in UBR1 allowing for partial function.

Topics: Abnormalities, Multiple; Adolescent; Anus, Imperforate; Diagnosis, Differential; Ectodermal Dysplasia; Exocrine Pancreatic Insufficiency; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Male; Nose; Pancreatic Diseases; Phenotype; Syndrome

Here we apply objective, reliable methods of dysmorphology diagnosis to a patient with Johanson-Blizzard syndrome (MIM #243800). Using an extensive normative database, we computed standardized scores on a graded continuum for operational definitions of nasal alar hypoplasia, a commonly observed feature of this condition.. Most of these measurements in this case were greater than 2 standard deviations below the mean, adjusted for age, gender, and ethnicity.. This report provides a worked example of quantitative anthropometric assessment in the context of a case report, using tools that may find general application in clinical genetics.

Topics: Abnormalities, Multiple; Anus, Imperforate; Cephalometry; Ectodermal Dysplasia; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Infant; Intellectual Disability; Male; Nose; Pancreatic Diseases; Ubiquitin-Protein Ligases

Gorlin-Chaudhry-Moss syndrome (OMIM 233500) is a rare congenital malformation syndrome with the cardinal manifestations of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, ocular, and dental anomalies. Since 1960, only six affected individuals have been reported. We report a 4-year and 6-month-old female patient with this phenotype and review the clinical presentation of all patients known so far. Previously unreported malformations of the extremities, larynx, and nose are also described, expanding the phenotype of this rare syndrome. Array-CGH analysis did not show pathological deletions or duplications.

Topics: Abnormalities, Multiple; Child, Preschool; Chromosomes, Human, Pair 12; Craniofacial Abnormalities; DNA Copy Number Variations; Ductus Arteriosus, Patent; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Hypertrichosis; Infant; Larynx; Nose; Phenotype; Progeria; Toes

We present clinical features and genetic diagnosis in an Indian infant diagnosed with Johanson- Blizzard syndrome. This is a rare, autosomal recessive genetic condition with multi-system involvement and a characteristic facies. Molecular genetic testing is important to confirm the clinical diagnosis and offer prenatal diagnosis in future pregnancies.

Topics: Anus, Imperforate; Ectodermal Dysplasia; Female; Genetic Testing; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; India; Infant, Newborn; Intellectual Disability; Nose; Pancreatic Diseases

Topics: Adult; Anus, Imperforate; Ectodermal Dysplasia; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Male; Nose; Pancreatic Diseases; Pancytopenia; Vitamin B 12; Vitamin B 12 Deficiency; Young Adult

Oral rehabilitation of a child with Johanson-Blizzard syndrome (JBS).. JBS is an extremely rare inherited disorder characterized by unusually small nose that appears 'beak shaped' due to the absence (aplasia) or underdevelopment (hypoplasia) of the nostrils (nasal alae), abnormally small, malformed primary (deciduous) teeth and misshapen or absent secondary (permanent) teeth, hearing disorder, hypothyroidism, dwarfism, malabsorption and mental retardation. It is sometimes described as a form of ectodermal dysplasia.. Oral findings in JBS are very obscure in the literature. The present report describes oral findings in an 8 years old boy with JBS and his oral rehabilitation.. JBS has an emotional consequence for the affected individuals at early ages. Oral rehabilitation in this case had a very positive impact on the child's mind.. Early identification and treatment of this disease is of great importance to rehabilitate the patient on functional, esthetic and psychological front.

Topics: Anodontia; Anus, Imperforate; Cheilitis; Child; Crowns; Dental Caries; Denture, Partial, Fixed; Ectodermal Dysplasia; Facies; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Incisor; Intellectual Disability; Male; Nose; Pancreatic Diseases; Pulpotomy; Space Maintenance, Orthodontic; Tongue

Mutations of the short stature homeobox-containing (SHOX) gene on the pseudoautosomal region of the sex chromosomes cause short stature. GH treatment has been recently proposed to improve height in short patients with SHOX deficiency. The aim of this study was to evaluate GH secretion and analyze growth and safety of recombinant human GH (rhGH) therapy in short children and adolescents with SHOX deficiency.. We studied 16 patients (10 females; 9.7 ± 2.9 years old; height -2.46 ± 0.82 standard deviation score, SDS) with SHOX deficiency. All subjects underwent auxological evaluations, biochemical investigations, and were treated with rhGH (0.273 ± 0.053 mg/kg/week).. Impaired GH secretion was present in 37.5% of the studied subjects. Comparing baseline data with those at the last visit, we found that rhGH treatment improved growth velocity SDS (from -1.03 ± 1.44 to 2.77 ± 1.95; p = 0.001), height SDS (from -2.41 ± 0.71 to -1.81 ± 0.87; p < 0.001), and IGF-1 values (from -0.57 ± 1.23 to 0.63 ± 1.63 SDS, p = 0.010) without affecting body mass index SDS. Height SDS measured at the last visit was significantly correlated with chronological age (r = -0.618, p = 0.032), bone age (r = -0.582, p = 0.047) and height SDS (r = 0.938, p < 0.001) at the beginning of treatment. No adverse events were reported on rhGH therapy which was never discontinued.. These data showed that impaired GH secretion is not uncommon in SHOX deficiency subjects, and that rhGH therapy may be effective in increasing height in most of these patients independent of their GH secretory status, without causing any adverse events of concern.

Topics: Adolescent; Body Height; Child; Child, Preschool; Female; Fingers; Growth Disorders; Growth Hormone; Hair Diseases; Homeodomain Proteins; Human Growth Hormone; Humans; Langer-Giedion Syndrome; Male; Nose; Osteochondrodysplasias; Recombinant Proteins; Short Stature Homeobox Protein

Johanson-Blizzard syndrome is a rare autosomal recessive disorder, characterized by exocrine pancreatic deficiency and a wide range of other abnormalities. We present here an infant with failure to thrive, exocrine pancreatic deficiency, short stature and developmental delay, cutis aplasia on the scalp, aplasia of alae nasi, hypospadias, hypothyroidism, myxomatous mitral valve, and patent ductus arteriosus. Molecular studies revealed a novel homozygous nonsense mutation in exon 38 of the UBR1 gene, which confirmed the diagnosis of Johanson-Blizzard syndrome. It should be acknowledged that the combination of exocrine pancreatic insufficiency and nasal wing hypo-aplasia is pathognomonic for this syndrome. Prompt diagnosis and exact monitoring of the patients with JBS are required to avoid further complications.

Topics: Anus, Imperforate; Codon, Nonsense; Deafness; Ectodermal Dysplasia; Exocrine Pancreatic Insufficiency; Exons; Growth Disorders; Hearing Loss, Sensorineural; Homozygote; Humans; Hypothyroidism; Infant; Intellectual Disability; Male; Nose; Pancreatic Diseases; Ubiquitin-Protein Ligases

Johanson-Blizzard syndrome (JBS; OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, facial dysmorphism with the characteristic nasal wing hypoplasia, multiple malformations, and frequent mental retardation. Our previous work has shown that JBS is caused by mutations in human UBR1, which encodes one of the E3 ubiquitin ligases of the N-end rule pathway. The N-end rule relates the regulation of the in vivo half-life of a protein to the identity of its N-terminal residue. One class of degradation signals (degrons) recognized by UBR1 are destabilizing N-terminal residues of protein substrates.. Most JBS-causing alterations of UBR1 are nonsense, frameshift or splice-site mutations that abolish UBR1 activity. We report here missense mutations of human UBR1 in patients with milder variants of JBS. These single-residue changes, including a previously reported missense mutation, involve positions in the RING-H2 and UBR domains of UBR1 that are conserved among eukaryotes. Taking advantage of this conservation, we constructed alleles of the yeast Saccharomyces cerevisiae UBR1 that were counterparts of missense JBS-UBR1 alleles. Among these yeast Ubr1 mutants, one of them (H160R) was inactive in yeast-based activity assays, the other one (Q1224E) had a detectable but weak activity, and the third one (V146L) exhibited a decreased but significant activity, in agreement with manifestations of JBS in the corresponding JBS patients.. These results, made possible by modeling defects of a human ubiquitin ligase in its yeast counterpart, verified and confirmed the relevance of specific missense UBR1 alleles to JBS, and suggested that a residual activity of a missense allele is causally associated with milder variants of JBS.

Topics: Adolescent; Anus, Imperforate; Child; Deafness; Ectodermal Dysplasia; Female; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Mutation; Mutation, Missense; Nasal Mucosa; Nose; Pancreatic Diseases; Signal Transduction; Ubiquitin-Protein Ligases

Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency, hypoplastic or aplastic nasal alae, cutis aplasia on the scalp, and other features including developmental delay, failure to thrive, hearing loss, mental retardation, hypothyroidism, dental abnormalities, and anomalies in cardiac and genitourinary systems. More than 60 cases of this syndrome have been reported to date. We describe the case of a male infant with typical symptoms of JBS. In addition, a new clinical feature which has not previously been documented, that is anemia requiring frequent blood transfusions and mild to moderate thrombocytopenia was observed. A molecular study was performed which revealed a novel homozygous UBR1 mutation. Possible explanations for this new association are discussed.

Topics: Animals; Anus, Imperforate; Base Sequence; Deafness; DNA Mutational Analysis; Ectodermal Dysplasia; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Infant; Intellectual Disability; Male; Molecular Sequence Data; Nose; Pancreatic Diseases; Sequence Alignment

Many practitioners find the complexity of facial growth overwhelming and thus merely observe and accept the clinical features of atypical growth and do not comprehend the long-term consequences. Facial growth and development is a strictly controlled biological process. Normal growth involves ongoing bone remodeling and positional displacement. Atypical growth begins when this biological balance is disturbed With the understanding of these processes, clinicians can adequately assess patients and determine the causes of these atypical facial growth patterns and design effective treatment plans. This is the first of a series of articles which addresses normal facial growth, atypical facial growth, patient assessment, causes of atypical facial growth, and guiding facial growth back to normal.

Topics: Adaptation, Physiological; Biomechanical Phenomena; Bone Development; Bone Remodeling; Brain; Dental Arch; Face; Facial Bones; Growth Disorders; Humans; Mandible; Mandibular Condyle; Maxilla; Maxillofacial Development; Nose; Palate, Hard; Patient Care Planning; Periodontal Ligament; Pharynx; Skull Base; Tooth

Topics: Abnormalities, Multiple; Child, Preschool; Developmental Disabilities; Facies; Female; Fetal Growth Retardation; Foot Deformities, Congenital; Growth Disorders; Humans; Intellectual Disability; Nose

A subtle balanced translocation involving the terminal regions of 1q and 3p was identified in a large family by high-resolution karyotype analysis and confirmed by fluorescence in situ hybridization (FISH) analysis. In this family, segregation of a balanced t(1:3)(q42.3;p25) chromosome translocation led to two types of viable unbalanced complements. The proband inherited the derivative chromosome 3, resulting in partial trisomy of 1q and partial monosomy of 3p. A paternal uncle and cousin had the reciprocal rearrangement with a derivative of chromosome 1, resulting in partial monosomy for 1q and partial trisomy for 3p. While profound mental and physical retardation and congenital heart defects were characteristics for both rearrangements, facial dysmorphism was quite distinct for each imbalance. Individuals who had the derivative chromosome 3 had a long face, wide eyebrows, small palpebral fissures, hypertelorism, prominent glabella, a large tip of the nose, long philtrum with thin upper lip, and low set-ears. In contrast, family members with the derivative of chromosome 1 had a tall forehead with bifrontal narrowing, full and large cheeks, and large simple ears. Since the translocated segments are small and approximately equal in size in this family, it is not surprising that viability was seen in individuals with both types of adjacent-1 segregation. In this kindred, the ratio of normal to abnormal individuals born to balanced carriers is believed to be about 1:1.5. This suggests that the recurrence risk for carriers is 50%.

Topics: Abnormalities, Multiple; Adult; Chromosome Banding; Chromosome Segregation; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 3; Face; Family Health; Fatal Outcome; Female; Growth Disorders; Heart Defects, Congenital; Humans; Hypertelorism; In Situ Hybridization, Fluorescence; Infant; Infant, Newborn; Intellectual Disability; Karyotyping; Male; Nose; Pedigree; Translocation, Genetic

Johanson-Blizzard syndrome is a rare autosomal recessive disorder characterized by aplasia of the alae nasi, aplasia cutis, dental anomalies, postnatal growth retardation and pancreatic exocrine aplasia. Some endocrinological dysfunctions--growth hormone (GH) deficiency, hypothyroidism, and diabetes mellitus--are known to complicate this syndrome. We report here a Japanese infant with Johanson-Blizzard syndrome presenting with failure to thrive. Endocrinological examination by insulin-induced hypoglycemia showed not only the presence of GH deficiency, but also the loss of the glucagon secretion response to hypoglycemia. This complication suggests abnormal input of autonomic nerves to the islets of pancreas in Johanson-Blizzard syndrome.

Topics: Abnormalities, Multiple; Consanguinity; Exocrine Pancreatic Insufficiency; Failure to Thrive; Glucagon; Growth Disorders; Growth Hormone; Humans; Hypoglycemia; Infant; Insulin; Male; Nose; Pancreas; Scalp; Stimulation, Chemical; Syndrome

To describe the craniofacial morphology, dentition, and hand maturity in four siblings with Seckel syndrome.. Two boys and two girls, with Seckel syndrome. The children studied showed extreme growth retardation, severe microcephaly, bird-headed profile with receding chin, prominent nose, mental retardation, and extremely delayed skeletal maturation. The growth hormone axis and pituitary thyroid function was normal.. Skeletal and dental development were investigated from radiographic material, and a cephalometric analysis was performed from profile radiographs.. The craniums were remarkably small with an extremely short anterior cranial base (-4.3 to -5.5 standard units) and maxillary length (-3.8 to -4.7 SU). Differences in the morphology of the sella turcica were observed in girls and boys. Tooth maturity progressed normally. Tooth agenesis and tooth malformations were observed. Taurodontic root morphology was observed only in the girls. The approximate skeletal maturity showed retardation from 4 years 3 months to 4 years 11 months. Malformations of the hand-wrist skeleton occurred in the epiphyseal ossification centers of the middle phalangeal bone in the second, third, and fourth finger and in the distal phalangeal bone in the fifth finger. The epiphyseal ossification centers were lacking in the middle and distal phalangeal bones of the fifth finger.. The underlying gene defect in the affected children seemingly affects bone development and growth but not dental maturation and eruption.

Topics: Adolescent; Age Determination by Skeleton; Anodontia; Bone Development; Cephalometry; Child; Chin; Craniofacial Abnormalities; Epiphyses; Female; Fingers; Growth Disorders; Humans; Intellectual Disability; Male; Maxilla; Microcephaly; Nose; Odontogenesis; Sella Turcica; Skull Base; Syndrome; Tooth Abnormalities; Tooth Root; Wrist

We describe the case of a 13-year-old girl with an apparently de novo unbalanced translocation resulting in the presence of additional chromosomal material on the short arm of one X chromosome, which was detected by conventional G-banding studies. Fluorescence in situ hybridization (FISH) using the Chromoprobe Multiprobe-M protocol confirmed that the additional chromosomal material originated from chromosome 5. The karyotype of this patient is now established to be 46,X,der(X) t(X;5)(p22.3;q33), with a deletion of Xp22.3-pter and partial trisomy of 5q33-qter. The distal 5q trisomy genotype has been associated with clinical signs that include growth and mental retardation, eczema, craniofacial anomalies, and malformations of heart, lungs, abdomen, limbs, and genitalia. Our patient also has short stature, a prominent nasal bridge, a flat philtrum, a thin upper lip, dental caries, and limb and cardiac malformations, but she appears to be mildly affected compared with previously reported cases. This is the first case of distal 5q trisomy arising from a translocation with the X chromosome. Replication studies on this patient show that the derivative t(X;5) chromosome is late replicating in almost all cells examined, which indicates that this chromosome is preferentially inactivated. However, the translocated segment of chromosome 5 appears to be early replicating, which implies that the trisomic 5q segment is transcriptionally active. We cannot determine from these studies whether all or only some genes in this segment are expressed, but this patient's relatively mild clinical signs suggest that the critical region(s) that contribute to the distal 5q trisomy phenotype are at least partly suppressed. A review of other patients with X-chromosome translocations indicates that many but not all of them also have attenuated phenotypes. The mechanism of inactivation of autosomal material attached to the X chromosome is complex, with varying effects on the phenotype of the patients that depend on the nature of the autosomal chromatin. Replication studies are of limited utility in predicting expression of autosomal genes involved in X-chromosome translocations.

Topics: Abnormalities, Multiple; Adolescent; Chromosome Banding; Chromosome Painting; Chromosomes, Human, Pair 5; Female; Growth Disorders; Humans; Karyotyping; Nose; Translocation, Genetic; Trisomy; X Chromosome

We describe the clinical findings and natural history in two unrelated deeply mentally retarded females, now 28 and 20 years old respectively. Both presented prenatal growth retardation and severe postnatal growth retardation. Their craniofacial appearance is distinct with nasal hypoplasia, triangular mouth and thin lips. Both have a cleft palate and a retinal coloboma at the right eye. Motor development is below the age of 1 year with a complex neurological syndrome with axial hypotonia and spastic quadriplegia.

Topics: Abnormalities, Multiple; Cleft Palate; Coloboma; Craniofacial Abnormalities; Facies; Female; Growth Disorders; Humans; Intellectual Disability; Nose; Retina; Syndrome

We report on a boy with RAPADILINO syndrome. Including this report seven children with this syndrome have been described. The patient developed a poikilodermatous skin rash, suggesting overlap with the Rothmund-Thompson syndrome.

Topics: Abnormalities, Multiple; Diarrhea; Food Hypersensitivity; Growth Disorders; Humans; Infant; Intelligence; Joint Dislocations; Limb Deformities, Congenital; Male; Nose; Palate; Patella; Radius; Syndrome; Thumb

We report on two sibs with facial anomalies and developmental delay. Partial trisomy 2q was detected only after parental chromosome studies showed the father to carry a balanced interchromosomal insertion of 2 (q24.3-q32.1) into 5q.

Topics: Abnormalities, Multiple; Child, Preschool; Chromosome Inversion; Chromosomes, Human, Pair 2; Ear; Face; Female; Genitalia; Growth Disorders; Humans; Karyotyping; Kidney; Male; Nose; Trisomy

The feasibility and possible effects of palatal soft-tissue expansion in palatal repair were studied. A prospective longitudinal animal experiment was performed in 75 growing cats assigned to 5 groups. In 31 cats, a midline defect was made, and bipediced flaps were raised at the age of 8 weeks (stimulated Langenbeck operation) in order to create palatal scars. At the age of 14 weeks, custom-made tissue expanders were inserted palatally in 61 animals. Tissue expansion was performed by weekly inflation in 33 cats (16 without and 17 with scars) for an 8-week period. The remaining 28 cats (14 without and 14 with scars) served as sham groups. A control group was formed by 14 animals (without scars and without tissue expanders). Soft-tissue gain and its effects on maxillofacial growth and development were measured in the midsagittal plane on tracings from standardized lateral radiographs. The effects of the experimental interventions were evaluated for 8 weeks after removal of the tissue expanders. Not all the cats yielded results at all time periods. This study showed that soft-tissue expansion of palatal mucoperiosteum is feasible. The surgically induced scars did not cause significant differences between the different groups in the midsagittal plane, and the data from both expansion and sham groups could be pooled. Significant soft-tissue gain was achieved by the tissue-expansion technique. Iatrogenic side effects were significant anteroposterior growth retardation at the level of the bony palate and an increase in vertical growth of the anterior nasomaxillary height and the posterior skull height during active tissue expansion. After removal of the tissue expanders, some accelerated growth was found in the tissue expansion in the scarred tissue group, with initial correction of the abnormal growth at the cranial base level. It is concluded that palatal soft-tissue expansion is possible in growing cats. This technique, however, impaired maxillofacial growth and development.

Topics: Analysis of Variance; Animals; Cats; Cephalometry; Cicatrix; Feasibility Studies; Growth Disorders; Iatrogenic Disease; Longitudinal Studies; Maxilla; Maxillary Diseases; Maxillofacial Development; Mouth Mucosa; Nose; Palate; Periosteum; Prospective Studies; Radiography; Skull Base; Tissue Expansion; Tissue Expansion Devices; Vertical Dimension

We describe the seventh patient with the Floating-Harbor syndrome. Similar to previous cases in the literature this girl presented with proportionate intrauterine and postnatal growth retardation, normocephaly, triangular face with bulbous nose, long eyelashes, short upper lip, small vermilion border of upper lip, dorsally rotated ears, deep nuchal hair line, hirsutism, and clinodactyly of little fingers. She exhibited mental retardation and retarded speech development. Clinical symptoms and differential diagnosis of this rare syndrome are briefly discussed.

Topics: Abnormalities, Multiple; Child; Diagnosis, Differential; Eye Abnormalities; Female; Fetal Growth Retardation; Fingers; Growth Disorders; Hirsutism; Humans; Intellectual Disability; Mouth Abnormalities; Nose; Syndrome

Eight patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex, ranging in age from 4 to 33 months, were evaluated for the presence of dysmorphic features recently described as human immunodeficiency virus embryopathy. Birth data and growth charts were available. Growth failure, a prominent box-like head, large wide eyes, and a well-formed philtrum were seen in the majority of patients. The significance of hypertelorism, obliquity of eyes, long palpebral fissures, blue scleras, depressed bridge of nose, and prominent upper vermilion border is discussed.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Face; Female; Fetal Growth Retardation; Growth Disorders; Head; Humans; Infant; Male; Microcephaly; Nose; Pregnancy; Skull

A two-year-old boy and his mother with the Tricho-Rhino-Phalangeal syndrome type I were studied. The mother showed the complete triad of the syndrome with fine, sparse, slow-growing hair, pear-shaped nose and abnormal fingers. Cone-shaped epiphyses of the phalanges of the hands and shortening of the mesophalanges and of the first and fifth metacarpals were observed radiographically. With the exception of the extreme shortening of several phalanges and metacarpals the above mentioned symptoms were also present in the son.

Topics: Abnormalities, Multiple; Adult; Child, Preschool; Female; Fingers; Growth Disorders; Hair; Humans; Male; Nose; Radiography; Syndrome

Topics: Adolescent; Adult; Diagnosis, Differential; Female; Fingers; Genes, Dominant; Growth Disorders; Hair Diseases; Humans; Metatarsus; Nose; Syndrome

We report 21 patients with choanal atresia or ocular coloboma or both who have certain other associated anomalies, including congenital heart disease, postnatal growth deficiency, mental retardation and/or CNS anomalies, microphallus and cryptorchidism, and ear anomalies and/or deafness. Facial palsy, micrognathia, cleft palate, and swallowing difficulties were also common. It has not been possible to define a single etiology or a syndrome in these patients. We propose the mnemonic CHARGE (C-coloboma, H-heart disease, A-atresia choanae, R-retarded growth and retarded development and/or CNS anomalies, G-genital hypoplasia, and E-ear anomalies and/or deafness) to describe the features of this association.

Topics: Abnormalities, Multiple; Adult; Central Nervous System; Coloboma; Deafness; Developmental Disabilities; Ear; Eye Abnormalities; Female; Growth Disorders; Heart Defects, Congenital; Humans; Male; Nasopharynx; Nose; Sexual Dysfunction, Physiological

A 2.5 year-old boy is described with a typical tricho-rhino-phalangeal dysplasia type II (Langer-Giedion syndrome). The multiple exostoses appeared before the age of 2 years.

Topics: Abnormalities, Multiple; Child, Preschool; Face; Growth Disorders; Humans; Male; Nose; Psychomotor Disorders; Syndrome

A 14-month-old female with the Coffin-Siris syndrome is described. Typical features included underweight at birth, growth retardation, microcephaly, profound mental retardation, severe hypotonia with lax joints, feeding difficulties and frequent respiratory tract infections; sparce scalp hair, small nose, epicanthic folds, a prominent philtrum and full lips; a congenital heart defect; hypoplasia or aplasia of the distal phalanges of digits 2--5 and the corresponding nails, especially of the fifth fingers and toes, and aplasia of the middle phalanges of the little fingers and the second and fifth toes; severe delay in bone maturation. The proposita also showed hypoplasia of the lateral portions of both clavicles. Inheritance of the Coffin-Siris syndrome is possibly autosomal recessive.

Topics: Abnormalities, Multiple; Cardiomegaly; Face; Female; Fingers; Genes, Recessive; Growth Disorders; Hair; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Intellectual Disability; Lip; Microcephaly; Nails, Malformed; Nose; Radiography; Respiratory Tract Infections; Syndrome; Toes

Topics: Alopecia; Amino Acid Metabolism, Inborn Errors; Breast; Child; Cleft Lip; Dermatoglyphics; Ear; Ectodermal Dysplasia; Electrocardiography; Electroencephalography; Female; Follow-Up Studies; Growth Disorders; Humans; Lip; Male; Nails, Malformed; Nose; Skin Abnormalities; Sweating; Syndrome; Tooth Abnormalities

Topics: Abnormalities, Multiple; Adult; Cataract Extraction; Child; Disorders of Sex Development; Female; Growth Disorders; Humans; Intellectual Disability; Male; Microcephaly; Nose; Pyloric Stenosis; Syndactyly; Toes

Topics: Abnormalities, Multiple; Autoradiography; Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, 4-5; Cleft Palate; Growth; Growth Disorders; Humans; Infant; Intellectual Disability; Iris; Karyotyping; Male; Nose

Topics: Adolescent; Adult; Body Height; Bone Development; Child; Child, Preschool; Craniofacial Dysostosis; Female; Growth Disorders; Growth Hormone; Hernia, Inguinal; Humans; Intelligence; Karyotyping; Male; Nose; Pedigree; Puberty; Scrotum; Sex Chromosomes; Testis; Turner Syndrome