Crisponi/CISS1 syndrome: A case series

Abstract

Crisponi/CISS1 syndrome (MIM#272430) is a rare autosomal recessive disease characterized by major feeding difficulties, camptodactyly, and anhidrosis in early childhood; and the subsequent development of paradoxical cold-induced sweating and scoliosis later in life. The syndrome is caused by biallelic mutations in CRLF1 or, much less commonly, CLCF1. Although genotype/phenotype correlation has been elusive, it has been suggested that the level of the mutant protein may correlate with the phenotypic severity. However, we show in this series of 12 patients from four families, all previously unpublished, that the homogeneity of the recently described c.983dupG (p.Ser328Argfs∗2) mutation in CRLF1 was associated with a highly variable degree of severity, and that the phenotype significantly overlaps with the recently described COG6-related anhidrosis syndrome (MIM#615328). Another fifth previously unpublished family is also described with a novel mutation in CRLF1, c.605delC (p.Ala202Valfs*32). In Saudi Arabia the prevalence of the syndrome is probably underestimated due to the difficulty in making the diagnosis considering the complex phenotype with typical neonatal and evolutive features.

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

“…Most CS/CISS1 individuals originate from Europe, especially from the Mediterranean region [Italy mainland (4) and Sardinia (12 + 15 not tested for variants in CRLF1 ), Turkey (23), Spain (8), Lybia (3) and France (2)]. Others are from the Saudi Arabia (13), India, Pakistan, Japan, Australia, North or Central America . Although most of the disease‐associated CRLF1 variants are private and found only in single families, some variants occur frequently in distinct CS/CISS1 individuals from a specific geographical region (eg, c.226T>G and c.676_677dupA in Sardinia, c.708_709delinsT in Turkey, c.983dupG in Saudi Arabia and c.713dupC in Spain, Turkey, Roma population).…”

“…Up to now, 37 disease causing CRLF1 variants in 73 patients from 53 families have been reported in the medical literature. 4,[7][8][9][10]12,[17][18][19][20][21][22][23][24][25][26][27][28][29][30] In total, 88 CS/CISS1 individuals were identified, although 15 Sardinian CS/CISS1 individuals were not genetically analyzed because they died before CRLF1 had been found to be associated with the disease. 1 Table 1, we report here three novel variants in 3 of…”

Mutations in CRLF1 cause familial achalasia

“…Early onset feeding problems like in our patients are one of the characteristic symptoms of CS/CISS1 und usually come along with typical contractions of facial muscles and hyperthermia, symptoms so far absent in our patients. CS/CISS1 can be quite variable, even within the same family . Absence of scoliosis and cold‐induced sweating in our patients does not preclude CS/CISS1, since these symptoms typically evolve in adolescents.…”

Clinical and molecular genetic findings of Crisponi/cold‐induced sweating syndrome (CS/CISS) spectrum in patients from Turkey

“…3,8,26,27 The c.983dupG variant we detected in two unrelated families from Mardin, was previously reported from Saudi Arabia. 28,29 All patients harboring the c.776C>A variant, including the two unrelated patients reported herein, were also of Turkish origin. 16,28 One of the novel changes we report is c.713delC (Table 1) (Figure 2).…”

“…34,35 Interestingly, CRLF1-carrier mothers have been reported to suffer from gestational diabetes and preeclampsia in separate studies. 29,32,34,36,37 This may be a maternal sign of a pregnancy with an affected fetus. In our series, IUGR or oligohydramnios was noted in four patients with CRLF1 variants and in two patients with KLHL7 variants (Tables 2-4).…”