Crisponi/cold induced sweating syndrome type 1 (CS/CISS1; Mendelian Inheritance in Man [MIM] #272430), a rare autosomal recessive disorder, is possibly under-recognised due to its complex phenotype with likely misinterpretation of symptoms. Worldwide, there are fewer than 100 reported cases and we present the second Indian patient with a CRLF1 genetic mutation [1-4]. A 1½-month-boy presented with intermittent high-grade fever, episodic contractions of facial and neck muscles and feeding difficulties since birth. He was sixth born to a non-consanguineous healthy couple hailing from North India. There was history of two sibling deaths, a male and a female in third week of life. Both the babies were born at term gestation, had normal birth weight but associated with birth asphyxia followed by progressive feeding abnormalities and abnormal posturing. His three elder female siblings were all alive and healthy. There was history of one spontaneous abortion in mother. Antenatal course of the present pregnancy was uneventful; mother received 2 doses of tetanus toxoid. The baby was delivered vaginally at term gestation with a birth weight of 3.25 kg. He was non-vigorous with meconium stained liquor but cried after stimulation. He required NICU stay with oxygen therapy and intravenous antibiotics though all laboratory investigations including sepsis work up were within normal limits. At presentation at 1½ months of life, he had fever (103ºF), tachycardia, tachypnea, SpO2 of 98% at room air but clear chest. He was underweight (3.7 Kg) with normal length (60 cm) and head circumference (36.5cm). He had a round expressionless face (Fig.1a) with bilateral camptodactyly and clinodactyly with adduction of thumbs (Fig.1b) and overriding of the toes of both feet (Fig.1c). Neurological examination revealed a weak cry and decreased spontaneous motor activity. There were paroxysms of facial and neck muscle contraction leading to puckering of lips, tight eye closure, neck extension (Fig. 1d) along with inward rotation of the upper limbs and clenching of the hands lasting a few minutes. These episodes were associated with crying and often precipitated by tactile or painful stimulation with a frequency of 25-30 episodes during daytime. Episodes were absent during rest and sleep. Partial remission was obtained with clonazepam administration. Initially, possibilities of hypoxic ischemic encephalopathy, neonatal sepsis with meningitis, neonatal tetanus, Sandifer syndrome and inborn error of metabolism were considered. Laboratory investigations showed normal sepsis screen and sterile blood and urine cultures. Urine microscopy, cerebrospinal fluid examination, fundus, electroencephalo-graphy, chest X-ray, magnetic resonance imaging of brain, skeletal survey and ultrasound abdomen were normal. Metabolic screen (blood sugar, serum ammonia, arterial lactate, blood gas and urine ketones) was negative. ENT evaluation and X-ray temporo-mandibular joint (TMJ) ruled out TMJ ankylosis. 24-hour pH monitoring revealed mild gastro-esophageal reflux. Further literature search lead to a possibility of Crisponi/cold-induced sweating syndrome type 1 (CS/CISS1) and genetic analysis for its confirmation was done at the Institute of biomedical and genetic research, National research council, Italy. Molecular analysis carried out for all the nine Cytokine receptor like factor 1 (CRLF1) [NM_004750.4] coding regions (including the exon-intron junctions) by sequencing analysis of the PCR products showed the presence of a homozygous small deletion [c.120delA;p. (Ala41Leufs*2)] in exon 2. This variant　has very strong evidence of pathogenicity according to American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) 2015 guidelines classification (PVS1, PM2, PP4) and multiple algorithms predictions such as SIFT (damaging) and mutation taster (disease causing) [4]. Both parents as well as the two sisters were heterozygous, while the youngest sister was homozygous for the wild type allele, confirming the familial origin of the pathogenic variant. Genetic counselling was done for the family. The child was continued on orogastric (OG) feeds, anti-pyretics, lanzoprazole and clonazepam. He could gradually be weaned of OG feeds by 8 months of life but was subsequently lost to follow up.

Fig.1 A 1½-month-boy with 1a- round expressionless face; 1b- bilateral camptodactyly and clinodactyly with adduction of thumbs; 1c–overriding of the toes of both feet and 1d- paroxysms of facial and neck muscle contraction leading to puckering of lips, tight eye closure, neck extension.

CS/CISS1 is characterized by neonatal onset marked facial muscular contractions with trismus and abundant salivation, simulating a tetanic spasm precipitated by tactile stimulation or crying. There is associated intermittent hyperthermia, feeding problems (due to orofacial muscle spasms, poorly developed swallowing reflex, and associated gastroesophageal reflux (GER) and respiratory difficulties. A round face, broad nose with anteverted nostrils, small mouth, micrognathia and bilateral camptodactyly are typical [5]. It is usually lethal in the first few months of life. In rare surviving individuals, hyperthermia and muscle contractions may disappear after infancy while kyphoscoliosis and paradoxical cold induced sweating may develop towards the end of first decade; few may develop a mild psychomotor retardation [5,6]. Important differential diagnoses include neonatal tetanus (differentiated by absence of typical dysmor-phology), Stuve-Wiedemann syndrome (differentiated by lower limb bowing) and Freeman–Sheldon syndrome. CS/CISS1 is caused by variants in the CRLF1 gene. Thirty-seven disease causing CRLF1 pathogenic variants in 96 patients have been reported in the medical literature [1,4]. Although genotype/phenotype correlation has been elusive, it has been suggested that the level of the mutant protein may correlate with the phenotypic severity [4]. Treatment of CS/CISS1 is primarily symptomatic. Clonazepam for muscle spasms and moxonidine for cold induced sweating have been tried with variable response. Monitoring is recommended for development of kyphoscoliosis and psychomotor retardation [4,6]. The need for suspicion of CS/CISS1 in cases where the other common differential diagnosis have been ruled out and specially in presence of a suggestive family history is exemplified in the index case. Further, the role of genetic diagnosis for genetic counselling and preventing recurrence of the disease in the family cannot be over emphasized.