Exome sequencing in Crisponi/cold‐induced sweating syndrome–like individuals reveals unpredicted alternative diagnoses

Abstract

Crisponi/cold‐induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS‐like). Here, a whole exome sequencing approach in individuals with CS/CISS‐like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf‐Yang syndrome, and the early infantile epileptic encephalopathy‐11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow‐up.

Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

“…Nevertheless, it is known that SCN2A encodes the voltage‐gated sodium channel Nav1.2, an important neuronal sodium channel that is involved in initiation and conduction of action potentials in nerve and muscle. Mutated SCN2A was also described in a CS/CISS‐like individual, presenting dysmorphic features such as depressed nasal bridge, thermoregulatory instability, camptodactyly and contractions of the muscles . However, we cannot rule out that in this case the SCN2A mutation co‐occurs with a still unrecognized genetic defect.…”

“…CLIFAHDD individuals also show limb deformities including camptodactyly, foot abnormalities ranging from various defects to clubfoot. In 2019, Angius et al identified two persons with CS/CISS‐like phenotype harboring variants in NALCN . The affected individuals had no thermoregulatory problems but show typical dysmorphic features of CS/CISS including chubby cheeks and depressed nasal bridge.…”

“…MAGEL2 is an imprinted, maternally silenced, gene localized at 15q11‐13, in the Prader‐Willi syndrome (PWS, MIM#176270) region . Recently, Angius et al identified variants in MAGEL2 in two CS/CISS‐like individuals, showing camptodactyly, swallowing and feeding difficulties as well as dysmorphic features such as chubby cheeks. One of them had episodes of hyperthermia and profuse sweating.…”

“…In 2016, disease causing variants in kelch like family member 7 ( KLHL7 ) were detected in individuals with a CS/CISS‐like phenotype associated with retinitis pigmentosa (RP) . Recently, additional genes have been identified to be mutated in five other individuals with a CS/CISS‐like phenotype, namely sodium leak channel, non‐selective ( NALCN ), MAGE family member L2 ( MAGEL2 ) and sodium voltage‐gated channel alpha subunit 2 ( SCN2A ) . These genes are involved in the pathogenesis of other disorders with a dominant/de novo hereditary pattern.…”

“…In this respect, whole exome sequencing disclosed unpredicted differential diagnoses in people with a CS/CISS‐like phenotype, suggesting a high phenotypic overlap particularly in the neonatal period among the associated syndromes including congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, MIM#616266), Schaaf‐Yang (SHFYNG, MIM#615547), and early infantile epileptic encephalopathy‐11 (EIEE11, MIM#613721) syndromes. Thus, the diagnosis is rather difficult and strengthening the importance of the molecular diagnostic confirmation …”