Novel mutation in the DSG1 gene causes autosomal‐dominant striate palmoplantar keratoderma in a large Syrian family

Palmoplantar keratoderma (PPK) is a heterogenous group of skin disorders characterized by a persistent thickening of the palms of the hands and sometimes soles of the feet. PPK can be classified into many types, including diffuse, transgradient, and focal or striate, where the areas of palmoplantar skin are alternatively thickened. Mutations in four main genes, keratin 9 (KRT9), keratin 1 (KRT1), desmoglein (DSG1), and desmoplakin (DSP), have been associated with PPK. Striate PPK (SPPK) is commonly caused by mutations in DSG1. However, DSP and KRT1 gene mutations have been identified in some cases. In this study, fragment and sequencing analysis were performed for a large Syrian family with dominant SPPK. Segregation analysis showed a linkage with DSG1 gene. Direct Sanger sequencing identified a new mutation c.dup165_168AGCA. This frameshift mutation was heterozygous in all affected family members and absent in all normal individuals.     

Autosomal‐dominant biventricular arrhythmogenic cardiomyopathy in a large family with a novel in‐frame DSP nonsense mutation

A novel autosomal‐dominant in‐frame deletion resulting in a nonsense mutation in the desmoplakin (DSP) gene was identified in association with biventricular arrhythmogenic cardiomyopathy across three generations of a large Caucasian family. Mutations that disrupt the function and structure of desmosomal proteins, including desmoplakin, have been extensively linked to familial arrhythmogenic right ventricular cardiomyopathy (ARVC). Analysis of data from 51 individuals demonstrated the previously undescribed variant p.Cys81Stop (c.243_251delCTTGATGCG) in DSP segregates with a pathogenic phenotype exhibiting variable penetrance and expressivity. The mutation's pathogenicity was first established due to two sudden cardiac deaths (SCDs), each with a biventricular cardiomyopathy identified on autopsy. Of the individuals who underwent genetic screening, 27 of 51 were heterozygous for the DSP mutation (29 total with two obligate carriers). Six of these were subsequently diagnosed with arrhythmogenic cardiomyopathy. An additional nine family members have a conduction disorder and/or myocardial structural changes characteristic of an evolving condition. Previous reports from both human patients and mouse studies proposed DSP mutations with a premature stop codon impart mild to no clinical symptoms. Loss of expression from the abnormal allele via the nonsense‐mediated mRNA decay pathway has been implicated to explain these findings. We identified an autosomal‐dominant DSP nonsense mutation in a large family that led to SCD and phenotypic expression of arrhythmogenic cardiomyopathy involving both ventricles. This evidence demonstrates the pathogenic significance of this type of desmosomal mutation and provides insight into potential clinical manifestations.     

The wrinkly skin syndrome: a report of a case and review of the literature

A 2 1/2-year-old boy born of Jewish Moroccan parents is reported with physical findings of wrinkled skin on the dorsum of the hands and feet, with poor skin elasticity, syndactyly, mild kyphosis and poor muscle tone, the diagnosis being the wrinkly skin syndrome. All reported cases of this heritable disorder of connective tissue are reviewed and discussed in terms of genetics, ethnic clustering and differential diagnosis.     

Renal‐coloboma syndrome: Prenatal detection and clinical spectrum in a large family

Renal‐coloboma syndrome includes abnormalities in the urogenital and ocular systems as its primary manifestations, although it can be associated with abnormalities in other systems as well. This syndrome is caused by mutations in the PAX2 gene and is transmitted as an autosomal dominant trait. We report a family in which at least 7 members have manifestations of renal‐coloboma syndrome, including two in whom renal disease was diagnosed prenatally by ultrasound examination. A pathogenic frame‐shift mutation (619insG) was found in the PAX2 gene in affected family members, who show remarkable variability in both the ocular and renal manifestations of the syndrome. © 2001 Wiley‐Liss, Inc.     

Anticipation in a unique family with Charcot‐Marie‐Tooth syndrome and deafness: Delineation of the clinical features and review of the literature

Charcot‐Marie‐Tooth disease (CMT) is a clinically and genetically heterogeneous group of polyneuropathies characterized by degeneration of peripheral nerves, resulting in distal muscle atrophy, sensory loss, and deformities of hands and feet. We have studied 34 individuals in a large 84‐member four‐generation central Illinois family with autosomal dominant Charcot‐Marie‐Tooth and deafness. Nerve conduction velocities are consistent with type 1 CMT. Audiological evaluation revealed both auditory neuropathy and cochlear involvement in affected individuals. There is increasing clinical severity and younger age of onset of CMT and deafness with each progressive generation, suggestive of anticipation (P < 0.05). The proband, a female diagnosed at birth with hypotonia, bilateral vocal cord palsy, swallowing incoordination, and hearing impairment, died at age 18 months. Another individual died at the age of 3 months from hypotonia later attributed to CMT. Genetic analysis indicated that affected individuals in this family do not have the common 1.4 Mb duplication associated with type 1A CMT; however, all affected individuals have a unique G to C transversion at position 248 in coding exon 3 of the peripheral myelin PMP22 gene located on chromosome 17p11.2‐p12. This mutation is predicted to cause an Ala67Pro substitution in the second transmembrane domain of PMP22, consistent with the molecular cause of the CMT phenotype. However, it does not explain the cochlear component of the deafness, the clinical observation of anticipation, and other features in this family. © 2002 Wiley‐Liss, Inc.     

Clinical and functional characterization of a novel RASopathy‐causing SHOC2 mutation associated with prenatal‐onset hypertrophic cardiomyopathy

SHOC2 is a scaffold protein mediating RAS‐promoted activation of mitogen‐activated protein kinase (MAPK) signaling in response to extracellular stimuli. A recurrent activating mutation in SHOC2 (p.Ser2Gly) causes Mazzanti syndrome, a RASopathy characterized by features resembling Noonan syndrome and distinctive ectodermal abnormalities. A second mutation (p.Met173Ile) supposed to cause loss‐of‐function was more recently identified in two individuals with milder phenotypes. Here, we report on the third RASopathy‐causing SHOC2 mutation (c.807_808delinsTT, p.Gln269_His270delinsHisTyr), which was found associated with prenatal‐onset hypertrophic cardiomyopathy. Structural analyses indicated a possible impact of the mutation on the relative orientation of the two SHOC2's leucine‐rich repeat domains. Functional studies provided evidence of its activating role, revealing enhanced binding of the mutant protein to MRAS and PPP1CB, and increased signaling through the MAPK cascade. Differing from SHOC2 ^S2G, SHOC2 ^{Q269_H270delinsHY} is not constitutively targeted to the plasma membrane. These data document that diverse mechanisms in SHOC2 functional dysregulation converge toward MAPK signaling upregulation.     

Saethre‐Chotzen syndrome: Notable intrafamilial phenotypic variability in a large family with Q28X TWIST mutation

Saethre‐Chotzen syndrome is an autosomal dominant disease characterized by craniosynostosis, ptosis, and limb and external ear abnormalities. Variable expressivity is a well‐known phenomenon in this disorder. A large Indian family has been recently identified as carrying a nonsense TWIST mutation (Q28 X) in 17 members, of whom 16 were examined in detail. Only 4 (25%) of the patients showed patent craniostenosis, namely, oxycephaly. The penetrance of craniosynostosis in this family is lower than previously reported in the literature. Fifteen patients (93%) had moderate to severe ptosis. Minor limb and external ear abnormalities were present in most patients. Eyelid features were the hallmark of the disease for 12 members of the family, suggesting that mutations in TWIST may lead to a phenotype with mainly palpebral features and no craniostenosis. The clinical analysis of this large family clearly illustrates the significant variable expressivity, probably related to haploinsufficiency because of the TWIST mutation. This phenotypic variability remains unclear but could be the result of modifier genes and/or genetic background effect, as noticed previously in the transgenic twist‐null heterozygous mice. © 2002 Wiley‐Liss, Inc.     

KPTN gene homozygous variant‐related syndrome in the northeast of Brazil: A case report

Alteration of the KPTN gene, responsible for the coding of kaptin (a protein involved in actin cytoskeletal dynamics), causes a syndrome characterized by macrocephaly, neurodevelopmental delay and epileptic seizures. We report the first Brazilian case of KPTN gene variation, previously described in nine subjects from four interlinked families from an Amish community in Ohio, two Estonian siblings and a 9‐year‐old boy from Kansas City. We report a case of KPTN‐related syndrome in a 5‐year‐old child which presented macrocephaly, muscular hypotonia, and global development delay. The neurological examination revealed below‐expected performance in coordination and balance tests, dyspraxia, and hand‐mouth synkinesia. Expressive language was characterized by phono‐articulatory imprecision, abundance of phonological processes and morphosyntactic immaturity. Neuropsychological assessment revealed intellectual disability with impairment of verbal and executive functions. Exome sequencing was performed. Analysis revealed a homozygous 2‐nucleotide duplication c.597_598dup p.(Ser200Ilefs*55) in the KPTN gene, which is predicted to lead to a translational frameshift and formation of a premature stop codon. The phenotypic profile is similar to the cases described in the other families. Presence of macrocephaly and delayed development indicate the possibility of KPTN gene variation. Genetic testing should be carried out at an early stage in order to reach a timely diagnosis.     

Exclusion of allelism of Noonan syndrome and neurofibromatosis-type 1 in a large family with Noonan syndrome-neurofibromatosis association

A large four-generation family with Noonan syndrome (NS) and neurofibromatosis-type 1 (NF1) was studied for clinical association between the two diseases and for linkage analysis with polymorphic DNA markers of the NF1 region in 17q11.2. Nonrandom segregation between NS and NF1 pheno-types was observed. Neurofibromatosis was tightly linked to NF1 markers, whereas Noonan syndrome was found not be allelic to NF1. These results suggest that two mutations at two independent but closely linked loci are the cause of neurofibromatosis-Noonan syndrome (NF-NS) association in this family. © 1996 Wiley-Liss, Inc.     

Phelan–McDermid syndrome: Clinical report of a 70‐year‐old woman

Phelan–McDermid or 22q13.3 deletion syndrome is characterized by global intellectual disability, childhood hypotonia, severely delayed or absent speech, features of autism spectrum disorder, without any major dysmorphisms or somatic anomalies. It is typically diagnosed before adolescence and data about adult patients are virtually absent. The expression of its phenotypical characteristics appears to be linearly related to the deletion size. Here, an intellectually disabled geriatric female patient is described with a long history of challenging behaviors in whom Phelan–McDermid syndrome was demonstrated. Detailed analysis of the patient's history and functioning resulted in a psychiatric diagnosis of atypical bipolar disorder and her behavior significantly improved upon maintenance treatment with a mood stabilizing agent. The present article confirms recent findings that atypical bipolar disorder may be part of the psychopathological phenotype of Phelan–McDermid syndrome, reason why careful etiological search is warranted, also in the geriatric population. © 2012 Wiley Periodicals, Inc.     

Missense mutation of TRPS1 in a family of tricho‐rhino‐phalangeal syndrome type III

We report a new Japanese family with tricho‐rhino‐phalangeal syndrome type III (TRPS III) who have a missense mutation (Arg908Gln) of theTRPS1 gene (TRPS1) in affected individuals of the family. This study supports the notion that TRPS III results from missense mutations in exon 6 of TRPS1. © 2001 Wiley‐Liss, Inc.     

GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson‐Golabi‐Behmel syndrome

Simpson‐Golabi‐Behmel syndrome (SGBS) is an X‐linked overgrowth syndrome caused by deletions in glypican 3 (GPC3). SGBS is characterized by pre‐ and postnatal overgrowth, a characteristic facial appearance, and a spectrum of congenital malformations which overlaps that of other overgrowth syndromes. We performed GPC3 deletion screening on 80 male patients with somatic overgrowth in the following categories: SGBS (n = 19), possible SGBS (n = 26), including families in which individuals had previously been diagnosed with other overgrowth syndromes, and Wiedemann‐Beckwith syndrome (WBS) (n = 35). Using exon‐specific PCR and Southern blot analysis, we identified seven GPC3 deletions. In most cases a clear X‐linked family history was not present. In two cases, GPC3 deletions were identified in patients belonging to pedigrees published previously as other overgrowth syndromes: one with a diagnosis of Sotos syndrome and the other Perlman syndrome with nephroblastomatosis. A third patient developed hepatoblastoma, a tumor type not previously described in SGBS. No GPC3 deletions were identified among the WBS patients. Direct sequencing of all GPC3 exons in the remaining 13 SGBS patients without GPC3 deletions did not identify any further mutations, raising the possibility of alternative silencing mechanisms and/or other genes in the pathogenesis of SGBS. Our results validate the clinical specificity of the facial appearance, skeletal/hand anomalies, and supernumerary nipples in patients with GPC3 deletions. Our data also suggest that nephroblastomatosis and hepatoblastoma are included in the phenotypic spectrum of GPC3 deletions and SGBS, underscoring the importance of tumor surveillance in these children. © 2001 Wiley‐Liss, Inc.     

Cowden syndrome: report of a large family with macrocephaly and increased severity of signs in subsequent generations

Hanssen AMN, Werquin H, Suys E, Fryns JP. Cowden syndrome: report of a large family with macrocephaly and increased severity of signs in subsequent generations.
Clin Genet 1993: 44: 281–286. © Munksgaard, 1993
We report Cowden syndrome in a large four-generation family, paying special attention to the apparently greater severity and earlier onset of signs and symptoms in subsequent generations. Macrocephaly was present in all affected individuals and was markedly progressive in three of six affected children of the fourth generation, and associated with slight to moderate delay in psychomotor development.     

Chest wall hamartoma with Wiedemann‐Beckwith syndrome: Clinical report and brief review of chromosome 11p15.5‐related tumors

A girl born with a left chest wall hamartoma, macroglossia, nevus flammeus of the middle forehead, and a small umbilical hernia developed left lower extremity hemihypertrophy by 1 year of age and is assumed to have Wiedemann‐Beckwith syndrome. Hamartoma of the bladder and a cardiac fibrous hamartoma have been reported previously in association with Wiedemann‐Beckwith syndrome. Infantile hamartomas are exceedingly rare and add to the spectrum of tumor formation in the syndrome. © 2001 Wiley‐Liss, Inc.     

Identification of a novel KCNQ1 mutation in a large Saudi family with long QT syndrome: clinical consequences and preventive implications

Congenital long QT syndrome (LQTS) is an inherited potentially fatal arrhythmogenic disorder that is characterized by prolonged corrected QT (QTc) interval. Mutations in three genes (KCNQ1, KCNH2, and SCN5A) account for the majority of the cases. However, 10 other genes are now known to be implicated in LQTS. In this work, we describe the clinical and molecular analysis in a large Saudi family with LQTS. Screening KCNQ1, KCNH2, and SCN5A genes in the proband, who presented with syncope, led to the identification of a heterozygous mutation (p.H258P) in KCNQ1. An extended clinical and genetic screening of the family identified 11 other members who were carriers for this mutation. All identified carriers had prolonged QTc intervals; yet, only two were symptomatic. Screening the family members for three LQTS modifiers (rs4657139 and rs16847548 in NOS1AP and KCNE1‐D85N) did not reveal a correlation with symptoms or QTc intervals. The electrocardiographic and molecular analysis stratified seven carriers at high risk of a cardiac event as they had a QTc of ≥500 ms and were carriers of a KCNQ1 mutation. Our work illustrates the importance of extended family screening in LQTS to identify silent carriers and hence adopt the most appropriate therapeutic and preventive intervention.