Giangiorgio Crisponi

Autosomal recessive disorder with muscle contractions resembling neonatal tetanus, characteristic face, camptodactyly, hyperthermia, and sudden death: a new syndrome?

This work describes an autosomal recessive syndrome observed over the past 25 years in 17 newborn babies (8 males, 9 females), from 12 different families in Southern Sardinia. This disorder is evident at birth and is characterized by marked muscular contraction of the facial muscles in response to tactile stimuli or during crying, with trismus and abundant salivation simulating a tetanic spasm. The contractions slowly disappear as the infant calms. There is also neck muscle hypertonia with a tendency to opisthotonus. All patients present facial anomalies such as large face, chubby cheeks, broad nose with anteverted nostrils, and long philtrum. The hands show bilateral camptodactyly. The clinical course in all patients was characterized by marked feeding difficulties and appearance of variable fever at about 38 degrees C, with peaks of irregular hyperthermia of over 42 degrees C, with onset ranging from birth to a few weeks. In some patients these symptoms were accompanied by generalized seizures. Death occurred after a period of a few weeks to some months and coincided with fever above 42 degrees C. Laboratory investigations performed in all of these cases did not give any useful pathogenetic indications. Only patients 10 and 16 are still alive today. Patient 10 is now 14 years old. She presents slow regression of the dystonic symptomatology, while dysthermia and mild psychomotor delay persist.

Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders

Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) are disorders caused by mutations in CRLF1. The two syndromes share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia, associated with death in most cases in the first years of life. To evaluate a potential genotype/phenotype correlation and whether CS and CISS1 represent two allelic diseases or manifestations at different ages of the same disorder, we carried out a detailed clinical analysis of 19 patients carrying mutations in CRLF1. We studied the functional significance of the mutations found in CRLF1, providing evidence that phenotypic severity of the two disorders mainly depends on altered kinetics of secretion of the mutated CRLF1 protein. On the basis of these findings, we believe that the two syndromes, CS and CISS1, represent manifestations of the same disorder, with different degrees of severity. We suggest renaming the two genetic entities CS and CISS1 with the broader term of Sohar–Crisponi syndrome.

Two sibs with Malpuech syndrome.

We report on two Italian brothers with facial clefting, hypertelorism, urogenital anomalies including micropenis, shawl scrotum, hearing loss, caudal appendage, and umbilical hernia. We have evaluated the two cases as Malpuech syndrome. This is an extremely rare autosomal recessive syndrome.

Two patients with varying combinations of sternal cleft, haemangiomas, midline abdominal raphe, coarctation of the aorta with a right aortic arch.

We report two patients, one with sternal cleft, haemangiomas, supraumbilical midline raphe and the other with a sternal cleft, haemangiomas, coarctation of the aorta with a right aortic arch.

Crisponi syndrome in an Indian patient: A rare differential diagnosis for neonatal tetanus

Niranjan Thomas, Sumita Danda,* Manish Kumar, Atanu Kumar Jana, Giangiorgio Crisponi, Alessandra Meloni, and Laura Crisponi Department of Neonatology, Christian Medical College, Vellore, India Clinical Genetics Unit, Christian Medical College, Vellore, India Servizio di Puericultura, Centro per lo studio delle malformazioni congenite, Casa di cura Sant’Anna, Cagliari University, Cagliari, Italy Istituto di Neurogenetica e Neurofarmacologia—Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Italy

Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa

Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) is a very rare autosomal-recessive disorder characterized by a complex phenotype with high neonatal lethality, associated with the following main clinical features: hyperthermia and feeding difficulties in the neonatal period, scoliosis, and paradoxical sweating induced by cold since early childhood. CS/CISS1 can be caused by mutations in cytokine receptor-like factor 1 (CRLF1). However, the physiopathological role of CRLF1 is still poorly understood. A subset of CS/CISS1 cases remain yet genetically unexplained after CRLF1 sequencing. In five of them, exome sequencing and targeted Sanger sequencing identified four homozygous disease-causing mutations in kelch-like family member 7 (KLHL7), affecting the Kelch domains of the protein. KLHL7 encodes a BTB-Kelch-related protein involved in the ubiquitination of target proteins for proteasome-mediated degradation. Mono-allelic substitutions in other domains of KLHL7 have been reported in three families affected by a late-onset form of autosomal-dominant retinitis pigmentosa. Retinitis pigmentosa was also present in two surviving children reported here carrying bi-allelic KLHL7 mutations. KLHL7 mutations are thus associated with a more severe phenotype in recessive than in dominant cases. Although these data further support the pathogenic role of KLHL7 mutations in a CS/CISS1-like phenotype, they do not explain all their clinical manifestations and highlight the high phenotypic heterogeneity associated with mutations in KLHL7.

Expanding the mutational spectrum of CRLF1 in Crisponi/CISS1 syndrome.

Crisponi syndrome (CS) and cold‐induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis, and cold‐induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia associated with death in most cases in the first years of life. To date, 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey, and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalog all the 35 mutations, we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (https://grenada.lumc.nl/LOVD2/mendelian_genes/variants). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal‐recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome.

Trisomy 8 mosaicism in a patient born to a mother with 47,XXX

Trisomy8 isdetected in0.8%of spontaneousabortions [Hassold and Jacobs, 1984]. In liveborn infants trisomy 8 is almost always a mosaic condition. The frequency of mosaic trisomy 8 in newborn children is estimated at 1:30,000 [Nielsen and Wohlert, 1991]. The phenotypic variability of this syndrome is very high, ranging from minimal effects to severe malformations. However, patients with clinical manifestations often present with a recognizable clinical syndrome. Phenotypic characteristics include a long face with myopathic appearance, large ears, high prominent forehead, deep palmar and plantar creases, mental retardation, urogenital anomalies such as cryptorchism or hydronephrosis, bone and joint abnormalities, such as absent patellae, vertebral defects and camptodactyly, cardiovascular, ocular and gastrointestinal anomalies, and agenesis of the corpus callosum. Here,we report anunusual case ofmosaic trisomy8 in a girl born to a mother with karyotype 47,XXX. The patient showed most of the characteristics of this syndrome as: round face, hypertelorism, large ears, micrognathia, clinodactyly, camptodactyly, deep palmar and plantar creases, cryptorchidism, hydronephrosis, cardiovascular anomalies, agenesis of the corpus callosum, and mental retardation. Chromosome analysis using standard cytogenetic protocols and FISH (fluorescent in situ hybridization) was carried out in peripheral blood. Karyotype was: mos,47,XXþ8/46,XX (80% of examined metaphases trisomic for 8 chromosome, 20%withnormalkaryotype). The trisomy 8 mosaicism was confirmed by FISH using a whole chromosome 8 painting biotinilated probe (ONCOR, Inc., Gaithersburg, MD), perfomed according to the manufacturer’s protocol. The phenotype in trisomy 8 mosaicism syndrome can be highly variable [Habecker-Green et al., 1998]. Two hypotheses could explain this phenotypic variability of trisomy 8 mosaicism: first, tissue specific mosaicism may play a role; second, some individuals with trisomy 8 mosaicismmayhavederived it froma trisomic zygote, as reported by Robinson et al. [1995]. In these individuals the normal cell line would be a product of chromosomal loss. Therefore, in some individuals these normal cells could be expected to display uniparental disomy for chromosome 8. Since uniparental disomies have been shown to cause anomalies and mental retardation, it could, therefore, be a factor in phenotypic variability. Concerning the mechanism of formation, it is known that common autosomal trisomy (including mosaic) are due to errors in maternal meiosis in majority of the cases [Nicolaidis et al., 1998]. In trisomy 8 and trisomy 8 mosaicism, the studies carried out by Karadima et al. [1998] demonstrated that nondisjunction was probably due tomitotic (postzigotic) duplication.However, causes of chromosomal nondisjunction remains one of the significant questions in human genetics. The co-occurrence of 47,XXX in the mother and trisomy 8 in child could be only by chance. However, documentation of this patient may help future thinking about nondisjunction in these two disorders.

Isolated 'sign of the horns': a simple, pathognomonic, prenatal sonographic marker of Crisponi syndrome.

The case of a patient presenting with Crisponi syndrome recently hospitalized at our institution is described. During pregnancy a diagnosis of this syndrome was hypothesized following sonographic observation of the fetus with the hands showing ‘the sign of the horns’. Such a finding, if isolated, as in our case, may represent a simple, pathognomonic sonographic marker of Crisponi syndrome.

Warmth and nociceptive evoked potentials in cold-induced sweating syndrome type 1

Cold‐induced sweating syndrome type 1 (CISS1), is a rare, severe, autosomal recessive disease. It is characterized by morphological alterations and profuse sweating when ambient temperature is <22 °C. Although some individuals with CISS1 have decreased pain perception, no study has been conducted to evaluate thermal and pain sensations in these patients. The aim of this study was to assess the function of the nociceptive Aδ‐fibers and warmth C‐fibers by using CO2 laser‐evoked potentials (LEPs) in patients affected by CISS1.