Table 3.

Genes and Disorders of Interest in the Differential Diagnosis of Cold-Induced Sweating Syndrome / Crisponi Syndrome (CISS/CS)

GeneDisorderMOIClinical Characteristics & Overlapping FeaturesDistinguishing Features
KLHL7 PERCHING syndrome (OMIM 617055)ARInfants w/PERCHING syndrome may resemble those w/CISS/CS: both disorders are assoc w/paroxysmal oropharyngeal muscle contractions, swallowing & feeding difficulties, typical dysmorphic features, & camptodactyly. 1 Some persons w/PERCHING syndrome have hyperthermia & signs of retinitis pigmentosa.Unlike CISS/CS, few persons w/PERCHING syndrome survive childhood, & none has demonstrated cold-induced sweating.
LIFR 2Stüve-Wiedemann syndrome (STWS) (OMIM 601559)ARDysmorphic facial features; camptodactyly; severe sucking, swallowing, & feeding difficulties; stimulus-induced abnormal posturing & episodic facial contractions; laryngospasm causing respiratory distress; episodes of hyperthermia & sudden death. 2 Persistent heat intolerance & paradoxic cold-induced sweating. 3 Teens may manifest ↓ pain perception, signs of corneal injuries & scarring, early dental decay, & progressive kyphoscoliosis.Chondrodysplasia (manifest as congenital bowing of the long bones & ↓ joint mobility) is the main differentiating characteristic. (Note: STWS w/cold-induced sweating but w/o bowing of long bones has been reported. 4)
MAGEL2 Schaaf-Yang syndrome (SYS)AD 5Neurodevelopmental disorder similar to Prader-Willi syndrome. Manifest at birth w/generalized hypotonia, sucking & feeding difficulties, episodic severe respiratory distress & sleep apnea, & distal joint contractures. Children show marked DD & speech delay, & exhibit autistic behavior & ID.Infants w/SYS do not present w/characteristic dysmorphic features, episodic facial contractions, or stimulus-induced posturing typical of CISS/CS. SYS is not assoc w/hyperthermia or impaired thermoregulation.
MYH3 Distal arthrogryposis types 2A & 2B (DA2A/DA2B) (OMIM 193700 & 601680)ADSevere distal arthrogryposis & joint contractures; "whistling face" (intermittent facial muscle contraction & puckering of lips) that may resemble facial movements in young children w/CISS/CSIn infants w/CISS/CS (but not in DA2A/DA2B), puckering of lips is provoked by crying. In DA2A/DA2B, puckering of lips may occur when resting or sleeping. Microstomia (seen in DA2A/DA2B) is not assoc w/CISS/CS.
NALCN Congenital contractures of the limbs & face, hypotonia, & DD (CLIFAHDD) (OMIM 616266)ADStriking similarity w/CISS/CS: facial dysmorphisms, distal arthrogryposis & camptodactyly; micrognathia, impaired sucking, swallowing, & feeding w/need for long-term NG tube feeding; episodic stimulus-induced facial & oropharyngeal contractions, pursing of lips & excessive salivation, inspiratory stridor, & hypoxemia. Spells occur only during waking & incl excessive sweating in face, head, & upper trunk. 7Unlike CISS/CS, CLIFAHDD is assoc w/persistent severe axial hypotonia, precarious respiratory status, & DD.

AD = autosomal dominant; AR = autosomal recessive; CISS = cold-induced sweating syndrome; CS = Crisponi syndrome; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; NG = nasogastric


Melone et al [2014] reported a female age 33 years with features of STWS including cold-induced sweating, but without bowing of the long bones and complete chromosome 5 maternal isodisomy with an isozygous LIFR pathogenic variant (c.2170C>G, p.Pro724Ala). The proband’s mother was heterozygous for the c.2170C>G variant.


Schaaf-Yang syndrome is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the paternally derived MAGEL2 allele results in disease; a pathogenic variant on the maternally derived MAGEL2 allele does not result in disease because normally the maternally derived MAGEL2 allele is silenced).


From: Cold-Induced Sweating Syndrome Including Crisponi Syndrome

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